Gonadotropin-releasing hormone antagonists and their preparation and use

Abstract

The present invention relates to a gonadotropin-releasing hormone antagonist, which has antagonistic activity against gonadotropin-releasing hormone and can be used for the prevention or treatment of sex hormone-dependent diseases such as benign prostatic hyperplasia, uterine myoma, endometriosis, uterine fibroid, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, etc., or a prodrug thereof, or a pharma- ceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutical composition containing the same. TIFF2024540264000046.tif51170

Description

[Technical field]

[0001] The present invention belongs to the field of pharmaceutical technology, and relates to compounds and pharmaceutical compositions for preventing or treating sex hormone-dependent diseases, and their use and methods. In particular, the present invention relates to substituted pyrimidinedione compounds that can be used as gonadotropin releasing hormone receptor antagonists and their use. [Background technology]

[0002] The secretion of anterior pituitary hormones is feedback-regulated by peripheral hormones secreted from the target organs of the corresponding hormones and secretory-regulating hormones from the hypothalamus (which is the upper central organ of the anterior pituitary gland) (these hormones are generally called "hypothalamic hormones"). At present, nine types of hormones, including thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (GnRH), have been demonstrated to exist as hypothalamic hormones. These hypothalamic hormones are believed to exert their effects through receptors believed to exist in the anterior pituitary gland, and efforts are being made to find the expression of receptor genes specific to these hormones. Therefore, antagonists or agonists that act specifically and selectively on these receptors should control the action of hypothalamic hormones and the secretion of anterior pituitary hormones. Therefore, such antagonists or agonists are expected to be useful for the prevention or treatment of anterior pituitary hormone-dependent diseases.

[0003] As a drug that inhibits the GnRH receptor and the function of the GnRH receptor, superagonists have already been used as drugs for sex hormone-dependent diseases such as prostate cancer, breast cancer, and endometriosis. GnRH receptor superagonists bind to the GnRH receptor and exert an initial temporary gonadotropin secretion-stimulating effect, the so-called "flare-up phenomenon", and then inhibit the function by causing gonadotropin consumption and downregulation of the GnRH receptor. Therefore, GnRH receptor superagonists have the disadvantage of temporarily worsening the disease because they first promote the secretion of gonadotropin. On the other hand, the inhibitory mechanism of GnRH receptor antagonists (hereinafter referred to as "GnRH antagonists") is to inhibit the binding to the GnRH receptor, so they are expected to rapidly exert an inhibitory effect without secreting gonadotropin.

[0004] Currently, the compounds having known GnRH antagonist activity are mostly peptide compounds, such as GnRH-derived linear peptides (US Pat. No. 5,140,009 and US Pat. No. 5,171,835), bicyclic peptide derivatives (Journal of Medicinal Chemistry, Vol. 36, pp. 3265-3273 (1993)), decapeptide compounds modified at the 5th or 6th position (WO9846634A1), and decapeptide compounds modified at the 8th position (EP0277829B1).

[0005] Peptide compounds have many unsolved problems related to oral absorbability, dosage form, dose volume, drug stability, sustained action, and metabolic stability, etc. Considering the limitations of peptide GnRH receptor antagonists, some non-peptide GnRH receptor antagonists have already been proposed and have entered the development, clinical measurement, and sales stages, for example, Elagolix (also called NBI-56418 or ABT-620), a small molecule GnRH receptor antagonist jointly developed by Abbott and Neurocrine Biosciences Inc, which is currently in the third clinical phase, mainly applied to the treatment of endometriosis (phase III) and uterine fibroids (phase II).

[0006] Relugolix, also known as TAK-385, is a small molecule oral GnRH receptor antagonist developed by Japan's Takada Pharmaceutical company for the treatment of endometriosis, uterine fibroids and prostate cancer.

[0007] Although a large amount of meaningful research has been conducted in this field, there remains a need for continued research and development towards the development of more effective small molecule GnRH receptor antagonists. Summary of the Invention

[0008] The present invention provides a compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, TIFF2024540264000002.tif47170

[0009] Among them, X1 is independently selected from O or S; X2 and X3 are each independently selected from CR4 or N; X4 is a CR 3c or N, X5 is independently selected from CR6 or N; R1 is independently selected from H, D, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a C1-C6 haloalkyl group; R2 is H, D, C1-C6 alkyl group, R 2a Independently selected from C1 to C6 alkyl groups substituted with -O-; R 2a are independently selected from C1 to C6 haloalkyl groups; R 3a , R 3b , R 3c , R 3d , and R 3e are each independently selected from H, D, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, and a C3-C6 cycloalkyl group; R4 is independently selected from H, D, halogen, -CN, -NO2, -NH2, -OH, -SH, -COOH, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 alkylthio group, a C1-C6 alkylamino group, and a C3-C6 cycloalkyl group; R5 is independently selected from H, D, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkoxy group, and a C1-C6 haloalkoxy group; R6 is independently selected from H, D, a C1 to C6 alkyl group, a C3 to C6 cycloalkyl group, a C1 to C6 haloalkyl group, a C1 to C6 alkoxy group, and a C1 to C6 haloalkoxy group.

[0010] In some embodiments of the present invention, R1 is preferably independently selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isoamyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, and pentachloroethyl.

[0011] In some embodiments of the invention, R2 is preferably H, D, R 2aindependently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isoamyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl groups substituted with -O-; R 2a are preferably independently selected from a fluoromethyl group, a chloromethyl group, a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, a trichloromethyl group, a 2,2-difluoroethyl group, a 2,2-dichloroethyl group, a 3,3,3-trifluoroethyl group, a 3,3,3-trichloroethyl group, a pentafluoroethyl group, and a pentachloroethyl group.

[0012] In some embodiments of the present invention, R2 is more preferably R 2a R is independently selected from a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, and an n-hexyl group, each of which is substituted with -O-. 2a are more preferably independently selected from a fluoromethyl group, a chloromethyl group, a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, a trichloromethyl group, a 2,2-difluoroethyl group, a 2,2-dichloroethyl group, a 3,3,3-trifluoroethyl group, a 3,3,3-trichloroethyl group, a pentafluoroethyl group, and a pentachloroethyl group.

[0013] In some embodiments of the invention, R2 is more preferably independently selected from trifluoromethyl-O-methyl, trifluoromethyl-O-ethyl, trifluoromethyl-on-propyl, trifluoromethyl-on-butyl, trifluoromethyl-on-pentyl, trifluoromethyl-on-hexyl, trichloromethyl-O-methyl, trichloromethyl-O-ethyl, trichloromethyl-on-propyl, trichloromethyl-on-butyl, trichloromethyl-on-pentyl, and trichloromethyl-on-hexyl.

[0014] In some embodiments of the present invention, R 3a , R 3b , R 3c , R 3d , R 3e are preferably independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isoamyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, pentachloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0015] In some embodiments of the invention, R4 is H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isoamyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, fluoro. Methyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, 2,2-difluoroethyl group, 2,2-dichloroethyl group, 3,3,3-trifluoroethyl group, 3,3,3-trichloroethyl group, pentafluoroethyl group, pentachloroethyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, S-pentyloxy group, xyloxy group, 2-ethylbutoxy group, fluoromethoxy group, chloromethoxy group, difluoromethoxy group, dichloromethoxy group, trifluoromethoxy group, trichloromethoxy group, 2,2-difluoroethoxy group, 2,2-dichloroethoxy group, 3,3,3-trifluoroethoxy group, 3,3,3-trichloroethoxy group, pentafluoroethoxy group, pentachloroethoxy group, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, sec- and each independently is independently selected from a butylthio group, a tert-butylthio group, an n-pentylthio group, an S-pentylthio group, a hexylthio group, a 2-ethylbutylthio group, a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, an n-propylamino group, an isopropylamino group, an n-butylamino group, a sec-butylamino group, a tert-butylamino group, an n-pentylamino group, an S-pentylamino group, a hexamino group, a 2-ethylbutylamino group, a cyclopropyl group, and a cyclobutyl group.

[0016] In some embodiments of the present invention, R5 is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isoamyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, They are independently selected from a pentafluoroethyl group, a pentachloroethyl group, a methoxy group, an ethoxy group, a n-propoxy group, a isopropoxy group, a n-butoxy group, a sec-butoxy group, a tert-butoxy group, a n-pentyloxy group, a S-pentyloxy group, a hexyloxy group, a 2-ethylbutoxy group, a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, a fluoromethoxy group, a chloromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a 2,2-difluoroethoxy group, a 2,2-dichloroethoxy group, a 3,3,3-trifluoroethoxy group, a 3,3,3-trichloroethoxy group, a pentafluoroethoxy group, and a pentachloroethoxy group.

[0017] In some embodiments of the invention, R6 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isoamyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 2,2-difluoroethyl, 2,2-dichloro ... and wherein the halogen atom is independently selected from the group consisting of ethyl, 3,3,3-trichloroethyl, pentafluoroethyl, pentachloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, S-pentyloxy, hexyloxy, 2-ethylbutoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 3,3,3-trifluoroethoxy, 3,3,3-trichloroethoxy, pentafluoroethoxy, and pentachloroethoxy.

[0018] In some aspects of the present invention, there is provided a compound of formula (II), or a pharma- ceutically acceptable salt or stereoisomer thereof, TIFF2024540264000003.tif44170

[0019] Among them, X1 is independently selected from O or S; X2 and X3 are each independently selected from CR4 or N; X5 is independently selected from CH or N; R1 is independently selected from H, D, and a C1-C6 alkyl group; R2 is H, D, C1-C6 alkyl group, R 2aIndependently selected from C1 to C6 alkyl groups substituted with -O-; R 2a are independently selected from C1 to C6 haloalkyl groups; R 3a , R 3e are each independently selected from H, D, halogen, and a C1-C6 haloalkyl group; R4 is independently selected from H, D, halogen, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 alkylthio group, and a C1-C6 alkylamino group; R5 is independently selected from H, D, a C1-C6 alkyl group, and a C1-C6 alkoxy group.

[0020] In some aspects of the present invention, there is provided a compound of formula (II), or a pharma- ceutically acceptable salt or stereoisomer thereof, Among them, X1 is independently selected from O or S; X2 and X3 are simultaneously selected from N; X5 is independently selected from CH or N; R1 is independently selected from H, D, and a C1-C6 alkyl group, and the C1-C6 alkyl group is preferably selected from a methyl group and an ethyl group; R2 is H, D, C1-C6 alkyl group, R 2a C1-C6 alkyl groups substituted with -O-, wherein the C1-C6 alkyl groups are preferably selected from a methyl group, an ethyl group, an n-propyl group, and an n-butyl group; R 2a are independently selected from a C1-C6 haloalkyl group, the halogen is preferably selected from fluorine and chlorine, and the C1-C6 haloalkyl group is preferably selected from a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, and a trichloromethyl group; R 3a , R 3eare each independently selected from H, D, a halogen, and a C1-C6 haloalkyl group, the halogen being preferably selected from fluorine and chlorine, and the C1-C6 haloalkyl group being preferably selected from a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, and a trichloromethyl group; R4 is independently selected from a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 alkylthio group, and a C1-C6 alkylamino group, the C1-C6 alkoxy group is preferably selected from a methoxy group, an ethoxy group, an n-propoxy group, and an n-butoxy group, the C1-C6 haloalkoxy group is preferably selected from a fluoromethoxy group, a chloromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a trifluoromethoxy group, and a trichloromethoxy group, the C1-C6 alkylthio group is preferably selected from a methylthio group, an ethylthio group, an n-propylthio group, and an n-butylthio group, the C1-C6 alkylamino group is preferably selected from a methylamino group, an ethylamino group, an n-propylamino group, and an n-butylamino group, R5 is independently selected from H, D, a C1-C6 alkyl group, and a C1-C6 alkoxy group, the C1-C6 alkyl group being preferably selected from a methyl group, an ethyl group, an n-propyl group, and an n-butyl group, and the C1-C6 alkoxy group being preferably selected from a methoxy group, an ethoxy group, an n-propoxy group, and an n-butoxy group.

[0021] In some aspects of the present invention, there is provided a compound of formula (II), or a pharma- ceutically acceptable salt or stereoisomer thereof, Among them, X1 is independently selected from O or S; X2 and X3 are simultaneously selected from N; X5 is independently selected from CH or N; R1 is independently selected from H, D, and a C1-C6 alkyl group; R2 is R 2a R is a C1-C6 alkyl group substituted with -O-, R2 is preferably independently selected from a methyl group, an ethyl group, and a propyl group, R2a is a trifluoromethyl group, R 3a , R 3e are each independently selected from H, D, a halogen, and a C1-C6 haloalkyl group, the halogen being preferably selected from fluorine and chlorine, and the C1-C6 haloalkyl group being preferably selected from a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, and a trichloromethyl group; R4 is independently selected from a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 alkylthio group, and a C1-C6 alkylamino group, the C1-C6 alkoxy group is preferably selected from a methoxy group, an ethoxy group, an n-propoxy group, and an n-butoxy group, the C1-C6 haloalkoxy group is preferably selected from a fluoromethoxy group, a chloromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a trifluoromethoxy group, and a trichloromethoxy group, the C1-C6 alkylthio group is preferably selected from a methylthio group, an ethylthio group, an n-propylthio group, and an n-butylthio group, the C1-C6 alkylamino group is preferably selected from a methylamino group, an ethylamino group, an n-propylamino group, and an n-butylamino group, R5 is independently selected from H, D, a C1-C6 alkyl group, and a C1-C6 alkoxy group, the C1-C6 alkyl group being preferably selected from a methyl group, an ethyl group, an n-propyl group, and an n-butyl group, and the C1-C6 alkoxy group being preferably selected from a methoxy group, an ethoxy group, an n-propoxy group, and an n-butoxy group.

[0022] In some aspects of the present invention, there is provided a compound of formula (II), or a pharma- ceutically acceptable salt or stereoisomer thereof, Among them, X1 is independently selected from O or S; X2 and X3 are simultaneously selected from CR4; X5 is independently selected from CH or N; R1 is independently selected from H, D, and a C1-C6 alkyl group, and the C1-C6 alkyl group is preferably selected from a methyl group and an ethyl group; R2 is H, D, C1-C6 alkyl group, R 2a C1-C6 alkyl groups substituted with -O-, wherein the C1-C6 alkyl groups are preferably selected from a methyl group, an ethyl group, an n-propyl group, and an n-butyl group; R 2a are independently selected from a C1-C6 haloalkyl group, the halogen is preferably selected from fluorine and chlorine, and the C1-C6 haloalkyl group is preferably selected from a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, and a trichloromethyl group; R 3a , R 3e are each independently selected from H, D, a halogen, and a C1-C6 haloalkyl group, the halogen being preferably selected from fluorine and chlorine, and the C1-C6 haloalkyl group being preferably selected from a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, and a trichloromethyl group; R4 is independently selected from H, D, halogen, a C1-C6 alkoxy group, and a C1-C6 haloalkoxy group, the C1-C6 alkoxy group being preferably selected from a methoxy group, an ethoxy group, an n-propoxy group, and an n-butoxy group, the C1-C6 haloalkoxy group being preferably selected from a fluoromethoxy group, a chloromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a trifluoromethoxy group, and a trichloromethoxy group, the C1-C6 alkylthio group being preferably selected from a methylthio group, an ethylthio group, an n-propylthio group, and an n-butylthio group, and the C1-C6 alkylamino group being preferably selected from a methylamino group, an ethylamino group, an n-propylamino group, and an n-butylamino group.

[0023] R5 is independently selected from H, D, a C1-C6 alkyl group, and a C1-C6 alkoxy group, the C1-C6 alkyl group being preferably selected from a methyl group, an ethyl group, an n-propyl group, and an n-butyl group, and the C1-C6 alkoxy group being preferably selected from a methoxy group, an ethoxy group, an n-propoxy group, and an n-butoxy group.

[0024] In some aspects of the present invention, there is provided a compound of formula (II), or a pharma- ceutically acceptable salt or stereoisomer thereof, Among them, X1 is independently selected from O or S; X2 and X3 are simultaneously selected from CR4; X5 is independently selected from CH or N; R1 is independently selected from H, D, and a C1-C6 alkyl group, and the C1-C6 alkyl group is preferably selected from a methyl group and an ethyl group; R2 is H, D, C1-C6 alkyl group, R 2a C1-C6 alkyl groups substituted with -O-, wherein the C1-C6 alkyl groups are preferably selected from a methyl group, an ethyl group, an n-propyl group, and an n-butyl group; R 2a are independently selected from a C1-C6 haloalkyl group, the halogen is preferably selected from fluorine and chlorine, and the C1-C6 haloalkyl group is preferably selected from a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, and a trichloromethyl group; R 3a , R 3e are each independently selected from H, D, a halogen, and a C1-C6 haloalkyl group, the halogen being preferably selected from fluorine and chlorine, and the C1-C6 haloalkyl group being preferably selected from a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, and a trichloromethyl group; R4 is a C1-C6 haloalkoxy group, preferably a fluoromethoxy group, a chloromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a trifluoromethoxy group, or a trichloromethoxy group; R5 is independently selected from H, D, a C1-C6 alkyl group, and a C1-C6 alkoxy group, the C1-C6 alkyl group being preferably selected from a methyl group, an ethyl group, an n-propyl group, and an n-butyl group, and the C1-C6 alkoxy group being preferably selected from a methoxy group, an ethoxy group, an n-propoxy group, and an n-butoxy group.

[0025] In some aspects of the present invention, there is provided a compound of formula (III), a pharma- ceutically acceptable salt or stereoisomer thereof, TIFF2024540264000004.tif45170

[0026] Among them, X5 and X6 are independently selected from CR6 or N, and X5 and X6 are not simultaneously CR6 or N; R1 is independently selected from H, D, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a C1-C6 haloalkyl group; R2 is H, D, C1-C6 alkyl group, R 2a Independently selected from C1 to C6 alkyl groups substituted with -O-; R 2a are independently selected from C1 to C6 haloalkyl groups; R 3a , R 3e are each independently selected from H, D, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, and a C3-C6 cycloalkyl group; R4 is independently selected from H, D, halogen, -CN, -NO2, -NH2, -OH, -SH, -COOH, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 alkylthio group, a C1-C6 alkylamino group, and a C3-C6 cycloalkyl group; R5 is independently selected from H, D, a C1 to C6 alkyl group, a C3 to C6 cycloalkyl group, a C1 to C6 haloalkyl group, a C1 to C6 alkoxy group, a C3 to C6 cycloalkoxy group, and a C1 to C6 haloalkoxy group.

[0027] In some aspects of the invention, there is provided the following compound, or a pharma- ceutically acceptable salt or stereoisomer thereof: TIFF2024540264000005.tif189170

[0028] The present invention further provides a pharmaceutical composition comprising any one of the above compounds or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable vector. The pharmaceutical composition can be prepared into various pharma- ceutically acceptable dosage forms, such as tablets, capsules, oral liquids, granules, injections, or various sustained-release preparations. The pharmaceutical composition can be administered orally or parenterally (e.g., intravenously, subcutaneously, or topically). The dosage is adjusted appropriately according to the age, sex, and type of disease of the patient, but is usually about 1 to 200 mg per day.

[0029] The present invention further provides the use of the above-mentioned compound, its pharma- ceutically acceptable salt, stereoisomer, or drug composition in the preparation of a drug for preventing or treating sex hormone-dependent disease.The above-mentioned sex hormone-dependent disease includes sex hormone-dependent cancer, bone metastasis of sex hormone-dependent cancer, prostatic hyperplasia, prostate cancer, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovarian syndrome, acne, alopecia, Alzheimer's disease, infertility, irritable bowel syndrome, hormone-independent and LH-RH (luteinizing hormone-releasing hormone)-sensitive benign or malignant tumor or flushing.The above-mentioned sex hormone-dependent cancer is selected from prostate cancer, uterine cancer, breast cancer, and pituitary cancer.

[0030] In some embodiments of the present invention, the above compound, its pharma- ceutically acceptable salt, stereoisomer or pharmaceutical composition is used in the preparation of a reproductive regulator, a contraceptive, an ovulation inducer, or in the preparation of a drug for preventing postoperative recurrence of sex hormone-dependent cancer.

[0031] The compounds provided by the present invention have one or more of the following technical advantages:

[0032] 1. Has clear binding ability to human GnRHR, 2. It has a clear inhibitory effect on human GnRHR. 3. It has lower inhibitory activity against the human hERG potassium ion channel and less cardiac toxicity; 4.It can improve cell permeability in Caco-2 cells. 5. It can improve the drug's exposure and absolute bioavailability in the body, and has excellent pharmacokinetic properties. 6. Higher drug concentrations in the target organ, the pituitary gland. Definition and Explanation

[0033] Unless otherwise specified, the following terms and phrases used herein shall have the following meanings: Terms or phrases not specifically defined are not to be considered indefinite or unclear, but are to be understood in their general sense. Trade names appearing herein refer to the corresponding product or its active ingredients.

[0034] The term "pharmaceutical acceptable" as used herein refers to compounds, compositions and / or dosage forms that are within the bounds of sound medical judgment and are suitable for use in contact with the tissues of human beings and animals, but without undue toxicity, irritation, allergic response or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0035] The term "pharmaceutical acceptable salt" described in the present invention refers to a salt of the compound of the present invention, which is prepared from the compounds found in the present invention and having specific substituents and a relatively non-toxic acid-alkali. When the compounds of the present invention contain a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutical acceptable acid addition salts include inorganic acid salts, organic acid salts, and further include salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Some specific compounds of the present invention contain a basic functional group, so they can be converted into any acid addition salt.

[0036] Some compounds of the present invention may possess asymmetric carbon atoms (optical centers) or double bonds. The racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.

[0037] The compounds of the present invention may have specific geometric or stereoisomeric forms. In the present invention, all compounds of this type, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and mixtures thereof, both racemic and other mixtures, such as mixtures enriched in enantiomers or diastereomers, are considered to be within the scope of the present invention. Substituents such as alkyl groups may have other asymmetric carbon atoms. All of these isomers and mixtures thereof are considered to be within the scope of the present invention.

[0038] The pharma- ceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds that contain an acid or base group. In general terms, the salts are prepared by reacting these compounds in their free acid or alkali form with an appropriate chemical amount of alkali or acid in water or an organic solvent or a mixture of both.

[0039] The term "pharmaceutically acceptable vector" refers to any formulation or vector vehicle representative of a vector capable of delivering an effective amount of an active agent of the present invention, not interfering with the biological activity of the active agent, and having no toxicity or side effects to the host or patient, including, but not limited to, binders, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizing agents, suspending agents, and the like.

[0040] The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those of skill in the art, or by methods analogous to those described herein, using the appropriate isotopically labeled reagent in place of the unlabeled reagent for further use.

[0041] Unless otherwise specified, the term "alkyl group" is intended to denote a saturated hydrocarbon group that may be straight or branched, may be mono-substituted (e.g., -CH2F) or poly-substituted (e.g., -CF3), and may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). For example, C1-C6 represents 1 to 6 carbons, C 1-10 is selected from C1, C2, C3, C4, C5 and C6, and examples of the alkyl group include a methyl group (Me), an ethyl group (Et), a propyl group (e.g., n-propyl group and isopropyl group), a butyl group (e.g., n-butyl group, isobutyl group, s-butyl group and t-butyl group), a pentyl group (e.g., n-pentyl group, isoamyl group, neopentyl group and 1-ethylpropyl group), a hexyl group (e.g., n-hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group and 2-ethylbutyl group), and the like.

[0042] Unless otherwise stated, the terms "halo" or "halogen," by themselves or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0043] "Haloalkyl group" is intended to include monohaloalkyl groups and polyhalogenated straight or branched alkyl groups. For example, the term "C1-C6 haloalkyl group" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl groups. Unless otherwise specified, illustrative examples of C1-C6 haloalkyl groups include, but are not limited to, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, and pentachloroethyl groups.

[0044] Unless otherwise specified, "alkoxy" refers to an alkyl group as defined above (including a cycloalkyl or haloalkyl group) having the specified number of carbon atoms connected through an oxygen bridge. Exemplary alkoxy groups include C 1-6Alkoxy groups include, for example, C1, C2, C3, C4, C5, and C6 alkoxy groups, C3, C4, C5, and C6 cycloalkoxy groups, and C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, S-pentyloxy, hexyloxy, and 2-ethylbutoxy groups. Examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy groups. Examples of haloalkoxy groups include, but are not limited to, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 3,3,3-trifluoroethoxy, 3,3,3-trichloroethoxy, pentafluoroethoxy, and pentachloroethoxy groups.

[0045] Unless otherwise specified, the term "alkylthio group" refers to an alkyl group attached to the remainder of the molecule through a sulfur atom, wherein the alkyl group has the meaning described herein. In some embodiments, the alkylthio group contains 1-6 carbon atoms, in other embodiments, the alkylthio group contains 1-4 carbon atoms, and in still other embodiments, the alkylthio group contains 1-3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described herein. Illustrative examples of alkylthio groups include, but are not limited to, methylthio (MeS, -SCH3), ethylthio (EtS, -SCH2CH3), n-propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, S-pentylthio, hexylthio, 2-ethylbutylthio, and the like.

[0046] Unless otherwise specified, the term "alkylamino" or "alkylamino group" refers to an amino group that is independently substituted with one or two alkyl groups, including "N-alkylamino group" and "N,N-dialkylamino group," in which alkyl group has the meaning described herein. In some embodiments, suitable alkylamino groups may be monoalkylamino groups or dialkylamino groups, in which each alkyl group contains 1-6 carbon atoms. Examples of such include, but are not limited to, N-methylamino group, N-ethylamino group, N,N-dimethylamino group, N,N-diethylamino group, N-propylamino group, isopropylamino group, n-butylamino group, sec-butylamino group, tert-butylamino group, n-pentylamino group, S-pentylamino group, hexamino group, 2-ethylbutylamino, and the like.

[0047] Unless otherwise specified, cycloalkyl groups include any stable cyclic or polycyclic hydrocarbon group, which may be saturated at any carbon atom, may be mono- or polysubstituted, and may be mono-, di- or polyvalent. Illustrative examples of these cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0048] Compounds were named artificially or with ChemDraw® software; commercially available compounds were named from the manufacturer's catalog. [Brief description of the drawings]

[0049] [Figure 1] 1 shows the average drug-time curve after intravenous administration (1 mg / kg) to SD rats. [Diagram 2] 1 shows the average drug-time curve after intragastric administration (12 mg / kg) to SD rats. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0050] The present invention will be further described below with reference to specific examples and test examples, but the scope of the present invention is not limited to these.

[0051] Example 1: Synthesis of Compound 1 TIFF2024540264000006.tif52170

[0052] Synthesis Route: TIFF2024540264000007.tif157170

[0053] Step 1: Synthesis of compound 1-1: Compound SM1 (90.0 g, 294 mmol) in toluene (2.36 L) was added with ethyl chloroformate (56.2 mL, 588 mmol) and reacted at 110° C. for 3 h. Ethyl chloroformate (56.2 mL, 588 mmol) was added again and reacted at 110° C. for 3 h, then more ethyl chloroformate (56.2 mL, 588 mmol) was added and reacted at 110° C. for another 6 h, cooled to 25° C., and concentrated in vacuum. The residue was added with 600 mL of methyl tert-butyl ether, filtered to collect the filter cake, washed with 100 mL of methyl tert-butyl ether, and dried to give compound 1-1 (107.57 g, 96.8%) as a yellow powder. MS m / z (ESI): 379 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ 1.36 (t, J=7.20 Hz, 3H), 1.42 (t, J= 7.20 Hz, 3H), 2.42 (s, 3 H), 4.31 (q, J= 7.20 Hz, 2 H), 4.40 (q, J = 7.20 Hz, 2H), 7.53 - 7.59 (m, 2H), 8.24 - 8.29 (m, 2H), 10.66 (s, 1H).

[0054] Step 2: Synthesis of compound 1-2: To a solution of compound 1-1 (107.57 g, 284.28 mmol, 1 eq) in DMF (3400 mL) was added K2CO3 (43.22 g, 312.71 mmol, 1.1 eq) and KI (51.91 g, 312.71 mmol, 1.1 eq). Then, to the mixture was added a solution of 2,6-difluorochlorobenzyl (55.46 g, 341.14 mmol, 1.2 eq) in DMF (190 mL). The mixture was stirred at 25 °C for 17 h. The precipitate thus formed was filtered and the filtrate was concentrated in vacuum. The residue was diluted with ethyl acetate (700 mL) and water (700 mL) and then extracted with ethyl acetate (300 mL × 2). The extract was washed with 500 mL water and 500 mL brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was stirred in MTBE (540 mL) at 25 °C for 30 min, and the precipitate was filtered to give compound 1-2 (127 g, 251.73 mmol, 88.55% yield), a pale yellow solid. MS m / z (ESI): 505 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ1.20 (s, 2H), 1.33 (t, J = 6.80 Hz, 4H), 2.40 (s, 3H), 4.18 - 4.34 (m, 4H), 4.98 (s, 2H), 6.86 (t, J = 8.00 Hz, 2H), 7.22 - 7.31 (m, 1H), 7.52 (d, J = 8.80 Hz, 2H), 8.25 - 8.30 (m, 2H).

[0055] Step 3: Synthesis of compounds 1-3: Compound 1-2 (50 g, 99.11 mmol, 1 eq), NBS (22.05 g, 123.88 mmol, 1.25 eq) and AIBN (1.63 g, 9.91 mmol, 0.1 eq) were stirred in ethyl acetate (600 mL) at 80 °C for 2 h. Further NBS (3.53 g, 19.82 mmol, 0.20 eq) and AIBN (162.74 mg, 991.08 μmol, 0.01 eq) were added to the system and heated at 80 °C for another 2 h. After cooling to room temperature, the reaction mixture was diluted with diluent (200 mL) and water (300 mL), and extracted (200 mL × 2). The extract was washed with 300 mL water and 500 mL brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound 1-3 (61.55 g crude) was obtained and used in the next step. MS m / z (ESI): 585, 583 [M+H] + .

[0056] Step 4: Synthesis of compounds 1-4: To a solution of compound 1-3 (40.0 g, 68.5 mmol) in ethyl acetate (400 mL), DIPEA (17.7 g, 137 mmol, 23.9 mL) and N-(2-methoxyethyl)methylamine (9.17 g, 103 mmol, 11.0 mL) were added and stirred at 25 °C for 16 h. LCMS showed that the starting material was already completely consumed. The mixture was washed with water (200 mL × 2) and brine (150 mL). The aqueous layer was extracted with ethyl acetate (200 mL). The organic layers were combined, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by silica gel (CH2Cl2:MeOH = 10:1) column chromatography to give compound 1-4 (60.0 g, 95.3%) as a yellow oil. MS m / z (ESI): 592 [M + H] + ; 1H NMR (400 MHz CDCl3), δ8.24 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.29 - 7.25 (m, 1H), 6.86 (t, J = 8.0 Hz, 2H), 5.01 (s, 2H), 4.23 - 4.20 (m, 4H), 3.63 (s, 2H), 3.37 - 3.36 (m, 2H), 3.28 (s, 3H), 2.46 (s, 2H), 2.08 (s, 3H), 1.35 - 1.19 (m, 6H).

[0057] Step 5: Synthesis of compounds 1-5: Compound 1-4 (60.0 g, 101 mmol) was placed in EtOH (900 mL) solution, Pd / C (12.0 g, 20.28 mmol, 10% purity, 0.2 eq) was added under N2 protection, then degassed under vacuum and replaced with H2 three times. The mixture was stirred at 25 °C under H2 atmosphere (25 psi) for 16 h. TLC (CH2Cl2:MeOH = 10:1, Rf = 0.2) showed that the starting material was completely consumed. The mixture was filtered, and the filter cake was washed with EtOH (500 mL) and THF (500 mL). The organic layer was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (150 mL), and the solvent was removed under reduced pressure. This process was repeated three times. Compound 1-5 (56.0 g, 90.5 mmol, 89.2% yield, 90.8% purity) was obtained as a brown oil. MS m / z(ESI):562[M+H] + ; 1 H NMR (400 MHz CDCl3), δ7.25 - 7.21 (m, 1H), 7.17 (d, J = 6.8 Hz, 2H), 6.83 (t, J = 8.0 Hz, 2H), 6.66 (d, J = 8.0 Hz, 2H), 4.99 (s, 2H), 4.23 - 4.18 (m, 4H), 3.59 (s, 2H), 3.34 - 3.31 (m, 2H), 3.26 (s, 3H), 2.39 (s, 2H), 2.05 (s, 3H), 1.32 - 1.18 (m, 6H).

[0058] Step 6: Synthesis of compounds 1-6: To a solution of compound 1-5 (56.0 g, 99.7 mmol) in dichloromethane (600 mL), DIPEA (25.7 g, 199 mmol, 34.7 mL) and CDI (32.3 g, 199 mmol) were added and stirred at 25 °C for 16 h. After the reaction was completed, DIPEA (64.4 g, 498 mmol, 86.8 mL) was added, and methoxyamine (41.6 g, 498 mmol, HCl) was added in several portions at 0 °C and stirred at 0-25 °C for 4 h. LCMS showed that the starting material was already completely consumed. The mixture was diluted with CHCl (1.00 L), washed with water (500 mL) and brine (500 mL), dried over NaSO, and the solvent was removed under reduced pressure. Purification by silica gel column chromatography gave compound 1-6 (64.0 g, 92.7 mmol, yield 93.0%, purity 92.0%) as a yellow oil. MS m / z (ESI): 635 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ7.64 (br.s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.25 - 7.21 (m, 1H), 6.85 (t, J = 8.4 Hz, 2H), 5.00 (s, 2H), 4.23 - 4.19 (m, 4H), 3.82 (s, 3H), 3.63 - 3.59 (m, 2H), 3.37 - 3.36 (m, 2H), 3.27 (s, 3H), 2.43 (s, 2H), 2.07 (s, 3H), 1.33 - 1.19 (m, 6H).

[0059] Step 7: Synthesis of compounds 1-7: To a solution of compound 1-6 (80.0 g, 126 mmol) in ethanol (700 mL), NaOH (2 M, 315.11 mL, 5 eq) was added, then stirred at 60 °C for 16 h. LCMS showed that the starting material was already completely consumed. After the mixture was decompressed, the solvent was removed and the pH was adjusted to 6-7 with aq. HCl. The aqueous layer was extracted with ethyl acetate (1.00 L x 10), the organic layers were combined, dried over Na2SO4, and the solvent was removed under reduced pressure to give compound 1-7 (67.0 g, 96.9 mmol, yield 76.9%, purity 87.8%) as a yellow solid. MS m / z (ESI): 607 [M+H] + ; 1 H NMR (400 MHz DMSO-d6), δ9.68 (br.s, 1H), 9.15 (s, 1H), 7.69 (d, J= 8.4 Hz, 2H), 7.41 - 7.37 (m, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.04 (t, J= 8.0 Hz, 2H), 4.89 (s, 2H), 3.97 - 3.93 (m, 2H), 3.62 (s, 3H), 3.49 - 3.46 (m, 2H), 3.18 (s, 3H), 2.83 (s, 2H), 2.38 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H).

[0060] Step 8: Synthesis of compounds 1-8: A solution of compound 1-7 (60.0 g, 98.9 mmol) and 3-amino-6-methoxypyridazine (25.0 g, 199 mmol) was dissolved in DMF (1800 mL), DIPEA (127 g, 989 mmol, 172 mL) and 1-propylphosphonic anhydride (189 g, 296 mmol, 176 mL, purity 50%) were added, and then the mixture was stirred at 25 °C for 3 h. LCMS showed that the starting material was already completely consumed. The mixture was poured into cold water (4.00 L) and the aqueous layer was extracted with ethyl acetate (2.00 L × 3). The combined organic layer was washed with water (1.00 L), dried with brine (1.00 L), Na2SO4, and the solvent was removed under reduced pressure to give compound 1-8 (64.0 g, 56.4 mmol, yield 57.0%, purity 62.9%) as a brown oil. MS m / z(ESI):714[M+H] + .

[0061] Step 9: Synthesis of compounds 1-9: A solution of compound 1-8 (64.0 g, 56.4 mmol, purity 62.9%) in methanol (900 mL) was added in portions to CH3ONa (30.5 g, 564 mmol) and stirred at 25 °C for 16 h. LCMS showed that the starting material was completely consumed. The mixture was added to cold aq. NH4Cl solution (1.50 L), extracted with ethyl acetate (1.50 L x 2), washed with water (1.00 L), brine (500 mL), dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Purification by silica gel column chromatography gave compound 1-9 (24.0 g, 32.3 mmol, yield 57.3%, purity 90.0%) as a yellow solid. MS m / z (ESI): 668 [M+H] + .

[0062] Step 10: Synthesis of compounds 1-10: A solution of compound 1-9 (4.80 g, 7.19 mmol) in tetrahydrofuran (200 mL) was added with a solution of 1-chloroethyl chloroformate (1.58 g, 11.0 mmol) in tetrahydrofuran (20 mL) and stirred at -70 to 25 °C for 3 h. LCMS showed that the starting material was already completely consumed. The mixture was added to 1.00 L of water and extracted with 1.00 L x 2 of ethyl acetate, the organic layer was washed with brine (500 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by pulping with methyl tert-butyl ether (500 mL), followed by filtration to give compound 1-10 (22.0 g, 30.7 mmol, yield 85.6%, purity 86.0%) as a yellow solid. MS m / z (ESI): 615 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ7.70 (br.s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 9.2 Hz, 1H), 7.40 - 7.25 (m, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 5.35 (s, 2H), 4.80 (s, 2H), 4.20 (s, 3H), 3.83 (s, 3H).

[0063] Step 11: Synthesis of compounds 1-11: Compound 1-10 (22.0 g, 35.8 mmol) and 2-(trifluoromethoxy)ethylamine (23.7 g, 143 mmol, HCl) in DMF (500 mL) were added with DIPEA (41.6 g, 322 mmol, 56.1 mL) and then stirred at 25° C. for 24 h. After the reaction was completed, the mixture was poured into 1.50 L of water, extracted with 1.00 L×3 of ethyl acetate, washed with 500 mL×2 of water, and the solvent was removed under reduced pressure. Compound 1-11 (15.5 g, 19.0 mmol, yield 53.2%, purity 87.0%) was obtained as a yellow solid. MS m / z(ESI): 708[M+H] + ;1 H NMR (400 MHz CDCl3), δ7.68 (br.s, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 9.2 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.16 (d, J = 9.2 Hz, 1H), 6.93 (d, J = 8.0 Hz, 2H), 5.36 (s, 2H), 4.20 (s, 3H), 4.03 - 4.01 (m, 2H), 3.91 (s, 2H), 3.82 (s, 3H), 3.90 - 3.89 (m, 2H).

[0064] Step 12: Synthesis of Compound 1: Compound 1-11 (5.00 g, 6.36 mmol, purity 90.0%) and paraformaldehyde (1.15 g, 12.7 mmol) were dissolved in methanol (150 mL), acetic acid (38.2 mg, 636 μmol, 36.4 μL) and NaBH3CN (1.60 g, 25.4 mmol) were added, and then stirred at 25 °C for 16 h. LCMS showed that the starting material was already completely consumed. The mixture was poured into aq. NH4Cl solution (1500 mL), extracted with ethyl acetate (1.00 L × 2), washed with water (500 mL), and brine (500 mL). Purification by column chromatography on silica gel (100% EtAOc) and SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ​​ETOH], B%: 45%-45%) gave compound 1 (4.98 g, 6.57 mmol, yield 34.4%, purity 95.2%) as a white solid. MS m / z (ESI): 722 [M+H] + ; 1H NMR (400 MHz DMSO-d6), δ9.60 (br.s, 1H), 9.07 (br.s, 1H), 7.74 - 7.70 (m, 3H), 7.57 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 9.2 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 5.37 - 5.22 (m, 2H), 4.09 (s, 3H), 4.03 - 4.00 (m, 2H), 3.80 - 3.68 (m, 2H), 3.63 (s, 3H), 2.65 (s, 2H), 2.09 (s, 3H). 19 F NMR: (400 MHz DMSO-d6), δ-58.744 ppm, -112.961 ppm.

[0065] Example 2: Synthesis of Compound 2 TIFF2024540264000008.tif44170

[0066] Synthesis Route: TIFF2024540264000009.tif161170

[0067] Synthesis of compound 2-1: Under N2 atmosphere, bis(pinacolato)diboron (75.1 g, 296 mmol, 1.20 eq) and Pd(dppf)Cl2 (7.21 g, 9.85 mmol, 0.04 eq) were added to a solution of SM2 (50.0 g, 246 mmol, 1.00 eq) and AcOK (120.87 g, 1.23 mol, 5.00 eq) in dioxane (600 mL). Stirred at 100 °C for 1.5 h. LCMS showed that SM2 was consumed and the main peak was detected. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated in vacuum to give the residue. The residue was purified using silica gel column chromatography (petroleum ether / ethyl acetate = 75 / 25) and petroleum ether / ethyl acetate = 5 / 1 (420 mL) at 25 °C for 2 h. Compound 2-1 (20 g, 77.5 mmol, yield 72.0%, purity 96.9%) was obtained as a white solid. MS m / z (ESI): 169 [M+H]+ ; 1 H NMR (400 MHz CDCl3), δppm 8.94 (s, 1 H), 8.38 - 8.40 (m, 1 H), 8.21 (d, J = 8.00 Hz, 1 H), 1.37 (s, 12 H).

[0068] Step 1: Synthesis of compound 2-2: Ethyl chloroformate (58.9 g, 542 mmol, 51.7 mL, 5.03 eq) was added to a solution of SM3 (20.0 g, 108 mmol, 1.00 eq) in toluene (200 mL). Stirred at 110 °C for 16 h. LCMS showed that SM3 was consumed and the main peak was detected. The mixture was concentrated under reduced pressure to give a residue that was used directly in the next step without purification. Compound 2-2 was obtained as a grey solid (27.6 g, 97.7 mmol, yield 90.5%, purity 91.1%). MS m / z (ESI): 258 [M+H] + .

[0069] Step 2: Synthesis of compound 2-3: At 0°C, NBS (20.6 g, 115.9 mmol, 1.10 eq) was added to a solution of compound 2-2 (27.1 g, 105.32 mmol, 1 eq) in CHCl3 (220 mL). The mixture was stirred at 0°C for 2 h, and LCMS showed that compound 2-2 was consumed and the main peak was already detected. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 94 / 6). Compound 2-3 (36.2 g, 93.0 mmol, yield 71.1%, purity 86.293%) was obtained as a white solid. MS m / z (ESI): 336,338 [M+H] + ; 1 H NMR (400 MHz DMSO-d6), δ ppm 4.20 - 4.29 (m, 4H), 2.22 (s, 3H), 1.24 - 1.33 (m, 6H).

[0070] Step 3: Synthesis of compounds 2-4: Compound 2-1 (33.92 g, 135.63 mmol, 2.4 eq), K2CO3 (15.62 g, 113.03 mmol, 2 eq) and Pd(dppf)Cl2 (4.14 g, 5.65 mmol, 0.1 eq) were added to a solution of compound 2-3 (19 g, 56.51 mmol, 1 eq) in dioxane (180 mL) and H2O (18 mL). The mixture was stirred at 80 °C for 18 h. LCMS showed that compound 2-3 was consumed and many new peaks had formed. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic layers were combined, washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / dichloromethane=30 / 70, Rf=0.26). Compound 2-4 (9.48 g, 22.80 mmol, yield 19.22%, purity 91.226%) was obtained as a yellow solid. MS m / z(ESI): 380[M+H] + .

[0071] Step 4: Synthesis of compounds 2-5: Compound 2-4 (6.00 g, 15.8 mmol, 1.00 eq), KI (2.89 g, 17.4 mmol, 1.10 eq) and K2CO3 (2.40 g, 17.4 mmol, 1.10 eq) were dissolved in DMF (50 mL) and 2,6-difluorochlorobenzyl (3.09 g, 19.0 mmol, 1.20 eq) was added, then the mixture was stirred at 25 °C for 6 h. LCMS showed that compound 2-4 was consumed and the main peak was formed. The mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL × 3), washed with brine (200 mL × 1), dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=80 / 20) to give compound 2-5 (7.26 g, 14.3 mmol, yield 90.6%, purity 99.8%) as a yellow oil. MS m / z(ESI): 506[M+H] + ; 1H NMR (400 MHz CDCl3), δ ppm 8.60 (d, J = 1.75 Hz, 1 H), 8.30 (d, J = 8.38 Hz, 1 H), 7.99 - 8.01 (m, 1 H), 7.24 - 7.30 (m, 1 H), 6.82 - 6.88 (m, 2 H), 4.97 (s, 2 H), 4.08 - 4.27 (m, 4 H), 2.40 (s, 3 H), 1.30 (m, 3 H), 1.18 - 1.25 (m, 3 H).

[0072] Step 5: Synthesis of compounds 2-6: To a solution of compound 2-5 (7.26 g, 14.4 mmol, 1.00 eq) in ethyl acetate (50 mL), NBS (3.07 g, 17.2 mmol, 1.20 eq) and AIBN (235.84 mg, 1.44 mmol, 0.1 eq) were added and then stirred at 80 °C for 16 h. NBS (3.07 g, 17.2 mmol, 1.20 eq) and AIBN (236 mg, 1.44 mmol, 0.10 eq) were added and then stirred at 80 °C for 4 h. NBS (3.07 g, 17.2 mmol, 1.20 eq) and AIBN (236 mg, 1.44 mmol, 0.10 eq) were added and then stirred at 80 °C for 16 h. LCMS showed that compound 2-5 was consumed and the main peak was formed. The mixture was diluted with ethyl acetate (100 mL) and washed with brine (50 mL×2). The aqueous layer was extracted with ethyl acetate (50 mL), the organic layer was dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was used directly in the next step without purification. Compound 2-6 (13 g, crude) was obtained as a brown oil. MS m / z (ESI): 584, 586 [M+H] + .

[0073] Step 6: Synthesis of compounds 2-7: To a solution of compound 2-6 (13.0 g, 22.3 mmol, 1.00 eq) in DMF (100 mL), DIEA (7.19 g, 55.6 mmol, 9.69 mL, 2.50 eq) was added, followed by the addition of Me2NH.HCl (2.39 g, 29.4 mmol, 1.32 eq) in portions and stirred at 25 °C for 5 h. LCMS showed that compound 2-6 was consumed and the main peak was formed. The mixture was poured into water (100 mL), extracted with ethyl acetate (150 mL × 3), washed with brine (100 mL × 2), dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60 / 40). Compound 2-7 (4.10 g, 6.30 mmol, yield 28.3%, purity 84.3%) was obtained as a yellow oil. MS m / z(ESI):549[M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 8 .76 (d, J = 1.38 Hz, 1 H), 8.24 - 8.30 (m, 2 H), 7.22 - 7.28 (m, 1 H), 6.81 - 6.86 (m, 2 H), 5.00 (s, 2 H), 4.18 - 4.26 (m, 4 H), 3.53 (s, 2 H), 2.10 (s, 6 H), 1.18 - 1.32 (m, 7 H).

[0074] Step 7: Synthesis of compounds 2-8: Compound 2-7 (3.10 g, 5.65 mmol, 1.00 eq) in EtOH (30 mL) was added with Pd / C (0.6 g, 1.13 mmol, 10% purity, 0.20 eq) under N2 protection, and the mixture was degassed under vacuum and replaced with H2 three times. Stirred at 25 °C for 34 h under H2 atmosphere (20 psi). LCMS showed that compound 2-7 was consumed and the main peak was formed. The reaction was filtered through diatomaceous earth, the filter cake was washed with 10 mL of ethanol, and the filtrate solvent was removed under reduced pressure. THF (30 mL) was added to the residue and removed by distillation, and this process was repeated three times. The residue was purified by silica gel (dichloromethane / methanol = 92 / 8) column chromatography. Compound 2-8 (1.80 g, 2.83 mmol, 48.8% yield, 81.4% purity) was obtained as a yellow oil. MS m / z(ESI):519[M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 8.04 (d, J = 2.13 Hz, 1 H), 7.47 (dd, J = 8.44, 2.31 Hz, 1 H), 7.20 - 7.27 (m, 1 H), 6.80 - 6.86 (m, 2 H), 6.52 (d, J = 8.51 Hz, 1 H), 4.98 (s, 2 H), 4.70 (s, 2 H), 4.16 - 4.26 (m, 4 H), 3.54 - 3.70 (m, 2 H), 2.12 (s, 6 H), 1.16 - 1.32 (m, 6 H).

[0075] Step 8: Synthesis of compounds 2-9: To a solution of compound 2-8 (1.20 g, 1.16 mmol, 1.00 eq) in THF (2 mL), CHNCO (822 mg, 11.6 mmol, 916 μL, 10.0 eq) was added and stirred at 50° C. for 12 h. LCMS showed that compound 2-8 was consumed and the main peak was formed. The reaction was evaporated under reduced pressure to remove the solvent to give a residue. The residue was purified by silica gel (dichloromethane / methanol=10 / 1) column chromatography. Compound 2-9 (1.01 g, crude product) was obtained as a yellow oil. MS m / z (ESI): 590 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 9.17 (s, 1 H), 8.80 (s, 1 H), 8.19 (d, J = 2.00 Hz, 1 H), 7.66 (dd, J= 8.50, 2.25 Hz, 1 H), 7.22 - 7.29 (m, 2 H), 6.93 (d, J = 8.38 Hz, 1 H), 6.82 - 6.86 (m, 2 H), 5.00 (s, 2 H), 4.18 - 4.29 (m, 4 H), 3.39 - 3.46 (m, 2 H), 3.15 - 3.34 (m, 2 H), 2.17 (s, 6 H), 1.32 (t, J = 7.13 Hz, 3 H), 1.23 - 1.27 (m, 3 H), 1.15 - 1.19 (m, 3 H).

[0076] Step 9: Synthesis of compounds 2-10: Compound 2-9 (1.01 g, 1.72 mmol, 1.00 eq) in EtOH (10 mL) was added to a solution of NaOH (2 M, 4.29 mL, 5.00 eq) and stirred at 60°C for 2 h. LCMS showed that compound 2-9 was consumed and a main peak was formed. The reaction solution was adjusted to pH=5-7 with HCl (1 mol / L, ca. 8 mL) at 0°C. The mixture was subjected to reduced pressure and freeze-drying to remove the solvent to obtain a residue. The residue was purified by silica gel (dichloromethane / methanol=87 / 13) column chromatography. Compound 2-10 (798 mg, 1.20 mmol, yield 70.1%, purity 84.7%) was obtained as a yellow solid. MS m / z(ESI):562[M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 9.43 (s, 1 H), 7.97 - 8.04 (m, 2 H), 7.51 - 7.60 (m, 2 H), 7.36 - 7.43 (m, 1 H), 7.04 (t, J = 8.00 Hz, 2 H), 4.89 (s, 2 H), 4.01 - 4.05 (m, 2 H), 3.11 - 3.21 (m, 3 H), 2.94 - 3.01 (m, 1 H), 2.44 (s, 6 H), 1.06 - 1.10 (m, 3 H), 0.94 - 1.04 (m, 3 H).

[0077] Step 10: Synthesis of compounds 2-11: Compound 2-10 (220 mg, 356 μmol, 1.00 eq), 3-amino-6-methoxypyridazine (80.2 mg, 641 μmol, 1.80 eq) were dissolved in DMF (6 mL), DIEA (460 mg, 3.56 mmol, 620 μL, 10.00 eq) and T3P (680 mg, 1.07 mmol, 635 μL, purity 50%, 3.00 eq) were added, and the mixture was stirred at 25 ° C for 17 h. Compound 12a (89.1 mg, 712 μmol, 2.00 eq), DIEA (460 mg, 3.56 mmol, 620 μL, 10.00 eq) and T3P (680 mg, 1.07 mmol, 635 μL, purity 50%, 3.00 eq) were added, and the mixture was stirred at 25 ° C for 1 h. Compound 12a (89.1 mg, 712 μmol, 2.00 eq), DIEA (460 mg, 3.56 mmol, 620 μL, 10 eq) and T3P (680 mg, 1.07 mmol, 635 μL, 50% purity, 3.00 eq) were added and stirred at 25 °C for another 1 h. LCMS showed that compound 2-10 was consumed and the main peak was formed. The mixture was poured into water (12 mL) and extracted with ethyl acetate (3 × 10.0 mL). The organic phase was washed with brine (3 × 30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. Compound 2-11 (270 mg, crude) was obtained as a yellow oil. MS m / z (ESI): 669 [M+H] + .

[0078] Step 11: Synthesis of compound 2: MeONa (218 mg, 4.04 mmol, 10.00 eq) was added to a solution of compound 2-11 (270 mg, 404 μmol, 1.00 eq) in MeOH (5 mL) at 0 °C and stirred at 25 °C for 14 h. LCMS showed that compound 2-11 was consumed and many peaks formed. The reaction was quenched with aq. NH4Cl solution (13 mL). The mixture was then extracted with ethyl acetate (3 × 10.0 mL) and methane chloride (3 × 10.0 mL). The organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel (dichloromethane / methanol=10 / 1) column chromatography and Welch xtimate C18 150×25 mm×5 μm column chromatography, mobile phase: [water (NH4HCO3)-ACN], B%: 10%-85%, 12 min. Compound 2 (25.0 mg, 40.06 μmol, yield 9.92%, purity 99.8%) was obtained as a white solid. MS m / z(ESI): 562[M+H] + ; 1 H NMR (400 MHz CD3OD), δ ppm 8.31 (d, J = 2.13 Hz, 1 H), 7.82 (dd, J =8.63, 2.38 Hz, 1 H), 7.64 (d, J = 9.13 Hz, 1 H), 7.32 - 7.49 (m, 2 H), 7.19 (d, J = 8.63 Hz, 1 H), 6.93 - 7.07 (m, 2 H), 5.26 - 5.49 (m, 2 H), 4.14 (s, 3 H), 3.29 - 3.36 (m, 4 H), 2.07 (s, 6 H), 1.19 (t, J =7.25 Hz, 3H). 19 F NMR: (400 MHz CDCl3) δ -114.827 ppm.

[0079] Example 3: Synthesis of Compound 3 Synthesis of fragment 1: TIFF2024540264000010.tif35170

[0080] Synthesis Route: TIFF2024540264000011.tif88170

[0081] Step 1-3: Compounds 1-1, 1-2, and 1-3 were synthesized using the same method as in Example 1.

[0082] Step 4: Synthesis of fragments 1-4: Compound 1-3 (56.5 g, 96.85 mmol, 1 eq), dimethylamine (23.69 g, 290.54 mmol, 26.62 mL, 3 eq, HCl) and DMF (245 mL) were added to a 500 mL one-neck round-bottom flask at 25 °C. Then, triethylamine (39.20 g, 387.39 mmol, 53.92 mL, 4 eq) was added and the reaction was continued with stirring for 2 h. The reaction was stopped, water (500 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 3), the liquid was separated, the organic phase was collected, the organic phase was washed with water (300 mL), dried over anhydrous Na2SO4, concentrated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain fragment 1-4 (38.97 g, 71.03 mmol, yield 73.34%), a pale yellow solid. MS m / z(ESI):548[M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 1.11 - 1.36 (m, 6H), 2.08 (s, 6H), 3.53 (s, 2H), 4.23 (m, 4H), 5.03 (s, 2H), 6.82 - 6.90 (t, J = 7.60 Hz, 2H), 7.23 - 7.31 (m, 1H), 7.67 (d, J= 8.80 Hz, 2H), 8.25 (d, J = 8.80 Hz, 2H).

[0083] Step 5: Synthesis of fragments 1-5: Fragment 1-4 solution (30 g, 54.8 mmol) and 4 mol / L HCl / dioxane (27.5 mL, 110 mmol) in EtOH (822 mL) was added with 10% Pd / C (50% wet, 9.73 g) and hydrogenated at 25°C under 15 psi H2 pressure for 1 h. The mixture was filtered with diatomaceous earth and the filtrate was neutralized with saturated aqueous NaHCO3 (200 mL). The combined filtrate was concentrated in vacuum, diluted with ethyl acetate (300 mL) and water (300 mL), and extracted with ethyl acetate (100 mL x 2). The extract was washed with brine, dried (Na2SO4), and concentrated in vacuum to give fragment 1-5 (28.79 g, 55.62 mmol, crude), a pale yellow oil. MS m / z (ESI): 518 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 1.17 (s, 3H), 1.31 (t, J = 7.20 Hz, 3H), 2.02 (s, 6H), 3.50 (s, 2H), 3.80 (br s, 2H), 4.15 - 4.25 (m, 4H), 5.00 (s, 2H), 6.66 (d, J = 8.38 Hz, 2H), 6.78 - 6.87 (m, 2H), 7.16 (d, J = 8.40 Hz, 2H) 7.20 - 7.26 (m, 1H).

[0084] Step 6: Synthesis of fragments 1-6: To a solution of fragment 1-5 (28.79 g, 55.62 mmol, 1 eq) in CHCl (720 mL), N,N-diisopropylethylamine (14.52 g, 112.36 mmol, 19.57 mL, 2.02 eq) and CDI (18.04 g, 111.25 mmol, 2 eq) were added. After stirring at 25 °C for 12 h, it was cooled to 0 °C. To the mixture, N-(2-methoxyethyl)methylamine (46.36 g, 555.12 mmol, 9.98 eq, HCl) and DIPEA (74.05 g, 572.92 mmol, 99.79 mL, 10.3 eq) were added and stirred at 25 °C for 12 h. The reaction was washed with saturated aqueous NaHCO (200 mL). The organic layer was separated and the aqueous layer was extracted with CHCl (200 mL × 2). The combined organic phase was washed with brine (400 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 30:1 to 5:1) to give fragment 1-6 (24.21 g, 40.99 mmol, 69.34% yield), as a pale yellow oil. MS m / z (ESI): 591 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 1.16 (s, 3H), 1.31 - 1.37 (m, 3H), 2.00 (s, 6 H), 3.50 (s, 1 H), 3.79 (s, 3 H), 4.19 (m, 4H), 4.99 (s, 2H), 6.83 (t, J= 7.60 Hz, 2H), 7.19 - 7.26 (m, 1H), 7.32 (d, J = 8.40 Hz, 2H), 7.51 (d, J = 8.80 Hz, 2H), 7.71 - 7.92 (m, 2H).

[0085] Step 7: Synthesis of Fragment 1: To a solution of fragment 1-6 (24.21 g, 40.99 mmol) in EtOH (500 mL), 2 mol / L NaOH (102 mL, 204.95 mmol) was added. After stirring at 60 °C for 6 h, 1 mol / L HCl (205 mL, 205 mmol) was added at 0 °C, and all were concentrated in vacuum. The residue was dissolved in 200 mL of ethanol and 200 mL of toluene, which was then concentrated. The residue was diluted with dry ethanol (200 mL), filtered, and the filtrate was concentrated under reduced pressure. Methyl tert-butyl ether (100 mL) was added to the residue, and the precipitate was collected by filtration, washed with methyl tert-butyl ether (50 mL), and dried to give fragment 1 (17.59 g, 31.3 mmol, 76.3%), a pale yellow solid. MS m / z (ESI): 563 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 1.05 - 1.10 (m, 3H), 2.44 (s, 6H), 3.62 (s, 3H), 3.90 - 4.17 (m, 4H), 4.90 (s, 2 H), 7.04 (t, J = 8.00 Hz, 2H), 7.16 (d, J = 8.00 Hz, 2H), 7.34 - 7.44 (m, 2H), 7.64 - 7.73 (d, J = 8.00 Hz, 2H), 9.22 (br s, 1H), 9.71 (br s, 1H).

[0086] Synthesis of compound 3: TIFF2024540264000012.tif49170

[0087] Synthesis Route: TIFF2024540264000013.tif82170

[0088] Synthesis of compound 3-1: To a solution of sodium difluorochloroacetate (17.4 g, 114.5 mmol) in DMF (25.0 mL) and water (6.00 mL), K2CO3 (8.80 g, 63.6 mmol) was added, and a solution of SM4 (5.00 g, 31.8 mmol) in DMF (25.0 mL) was added dropwise, and the system was stirred at 110 °C for 12 h. LC-MS showed that SM4 was completely consumed. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (200 mL × 3), and the combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to give compound 3-1 (0.30 g, 1.45 mmol, yield 4.55%) as a yellow oil. 1 H NMR (400 MHz CDCl3), δ ppm 7.96 - 7.92 (m, 1H), 7.58 - 7.56 (t, J= 7.2 Hz 1H), 7.32- 4.29 (m, 1H), 3.53 (t, J= 144 Hz, 1H).

[0089] Synthesis of compound 3-2: To a solution of compound 3-1 (0.30 g, 1.45 mmol) in MeOH (5.00 mL), Pd / C (0.03 g, 10% purity) was added, and the mixture was stirred at 25° C. for 16 h under a stream of hydrogen gas. LC-MS showed that compound 3-1 was completely consumed. The mixture was filtered and concentrated under reduced pressure to give crude compound 3-2 (172 mg, 971 μmol, 67.0% yield) as a yellow solid. MS m / z (ESI): 178 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 6.89 - 6.86 (m, 1H), 6.66 - 6.53 (m, 1H), 6.71 - 6.34 (t, J = 147.6 Hz, 1H).

[0090] Step 1: Synthesis of compound 3-3: A solution of compound 3-2 (170 mg, 959 μmol) and fragment 1 (300 mg, 533.25 μmol) in ACN (5.00 mL) was added with T3P (1.02 g, 1.60 mmol, 951.43 μL, purity 50%) and Et3N (134 mg, 1.33 mmol, 185 μL) and stirred at 40 °C for 2 h. LC-MS showed that fragment 1 was completely consumed. After adjusting the pH to 5-6 with sodium carbonate solution at 0 °C, it was then diluted with 20.0 mL of water and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 20 / 1 to 10 / 1) to obtain compound 3-3 (130 mg, 145 μmol, yield 27.3%, purity 81.0%) as a yellow oil. MS m / z (ESI): 722 [M+H] + .

[0091] Step 2: Synthesis of compound 3: Sodium methoxide (97.3 mg, 1.80 mmol) was added to a solution of compound 3-3 (130 mg, 180 μmol) in methanol (2.00 mL) and stirred at 25° C. for 2 h. LC-MS showed that compound 3-3 was completely consumed. The reaction system was subjected to layer extraction with 10.0 mL of ammonium chloride aqueous solution and 20.0 mL of ethyl acetate solution, and the organic phase was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, dichloromethane:MeOH=1 / 30-1 / 10). Compound 3 (71.0 mg, 99.8 μmol, yield 55.4%) was obtained as a yellow solid. MS m / z(ESI): 676[M+H] + ; 1H NMR (400 MHz CD3OD), δ ppm 7.71 - 7.69 (d, J = 8.80 Hz, 2H), 7.46 - 7.33 (m, 6H), 7.04 - 7.02 (t, J= 8.40 Hz, 2H), 7.06 - 6.73 (t, J = 131.6 Hz, 1H), 5.55 - 5.51 (d, J = 16.0 Hz, 1H), 5.41 - 5.37 (d, J = 16.0 Hz, 1H), 4.61(s, 1H), 4.26 - 4.17 (m, 2H), 3.74 (s, 3H), 2.17 (s, 6H).

[0092] Example 4: Synthesis of Fragment 2 TIFF2024540264000014.tif34170

[0093] Synthesis Route: TIFF2024540264000015.tif93170

[0094] Step 1: Synthesis of fragment 2-2: To a solution of compound 1-1 (5 g, 13.21 mmol, 1 eq) in DMF (150 mL) was added K2CO3 (2.01 g, 14.53 mmol, 1.1 eq) and KI (2.41 g, 14.53 mmol, 1.1 eq). Then, to the mixture was added a solution of 2-fluoro-6-(trifluoromethyl)benzyl bromide (55.46 g, 341.14 mmol, 1.2 eq) in DMF (190 mL). The mixture was stirred at 25 °C for 17 h. The precipitate thus formed was filtered and the filtrate was concentrated in vacuum. The residue was diluted with ethyl acetate (700 mL) and water (700 mL) and then extracted with ethyl acetate (300 mL × 2). The extract was washed with 500 mL water and 500 mL brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10-1-2 / 1). Fragment 2-2 (7.23 g, 10.30 mmol, 77.95% yield, 79% purity) was obtained as a yellow oil by TLC (petroleum ether:dichloromethane = 2:1, plate 2, Rf = 0.67). MS m / z (ESI): 555 [M+H] + .

[0095] Step 2: Synthesis of fragment 2-3: Fragment 2-2 (7.21 g, 13.00 mmol, 1 eq), AIBN (213.51 mg, 1.30 mmol, 0.1 eq) and NBS (2.89 g, 16.25 mmol, 1.25 eq) were reacted in ethyl acetate (100 mL) at 80 °C for 2 h. Additional NBS (1.39 g, 7.80 mmol, 0.6 eq) and AIBN (106.76 mg, 650.12 μmol, 0.05 eq) were added and the reaction was continued for another 2 h at 80 °C. Additional NBS (1.39 g, 7.80 mmol, 0.6 eq) and AIBN (106.76 mg, 650.12 μmol, 0.05 eq) were added and the reaction was continued for another 2 h at 80 °C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL) and water (300 mL) and extracted with ethyl acetate (200 mL×2). The extract was washed with 300 mL water and 500 mL brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product fragment 2-3 (7.22 g, crude) was obtained and used directly in the next step. MS m / z (ESI): 633 [M+H] + .

[0096] Step 3: Synthesis of fragment 2-4: Fragment 2-3 (7.20 g, 11.37 mmol, 1 eq), dimethylamine (3.84 g, 34.11 mmol, 4.32 mL, 40% purity, 3 eq) and DMF (300 mL) were added to a 500 mL one-neck round-bottom flask at 25 °C. Triethylamine (4.60 g, 45.48 mmol, 6.33 mL, 4 eq) was added and the reaction was continued with stirring for 2 h. The reaction was stopped, water (700 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 3), the liquid was separated, the organic phase was collected, the organic phase was washed with water (300 mL), dried over anhydrous Na2SO4, and the mixture was concentrated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain fragment 2-4 (5.12 g, 7.37 mmol, yield 64.81%, purity 86%), as a pale yellow solid. MS m / z(ESI):598[M+H] + .

[0097] Step 4: Synthesis of fragment 2-5: Fragment 2-4 (5.12 g) and 4 mol / L HCl / 1,4-dioxane (12.5 mL, 110 mmol) were reacted in EtOH (200 mL) with 10% Pd / C (50% wet, 5.0 g) under 15 psi H2 pressure at 25 °C for 6 h. The reaction was filtered through diatomaceous earth and the filtrate was neutralized with saturated aqueous NaHCO3 (200 mL). The filtrate was concentrated in vacuum, diluted with ethyl acetate (300 mL) and water (300 mL), and extracted with ethyl acetate (100 mL x 2). The organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuum to give fragment 2-5 (28.79 g, 55.62 mmol, 102% yield), as a pale yellow oil. MS m / z (ESI): 568 [M+H] + .

[0098] Step 5: Synthesis of fragment 2-6: To a solution of fragment 2-5 (4.18 g, 7.36 mmol, 1 eq) in CHCl (100 mL) was added N,N-diisopropylethylamine (14.52 g, 112.36 mmol, 19.57 mL, 2.02 eq) and CDI (4.78 g, 29.46 mmol, 4 eq). After stirring at 25 °C for 12 h, the mixture was cooled to 0 °C. After stirring at 25 °C for 12 h, the mixture was cooled to 0 °C. To the mixture was added methoxyamine hydrochloride (6.14 g, 73.50 mmol, 5.58 mL, 9.98 eq) and DIPEA (9.80 g, 75.85 mmol, 13.21 mL, 10.3 eq) and the mixture was stirred at 25 °C for 12 h. The reaction was washed with saturated aqueous NaHCO (200 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (200 mL×2). The combined organic phase was washed with brine (400 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, dichloromethane:methanol=30:1 to 5:1) to give fragment 2-6 (4.22 g, 6.59 mmol, 89.45% yield), as a pale yellow oil. MS m / z(ESI): 641[M+H] + .

[0099] Step 6: Synthesis of fragment 2: 2 mol / L NaOH (102 mL, 204.95 mmol) was added to a solution of fragment 2-6 (4.22 g, 6.59 mmol, 1 eq) in EtOH (500 mL). After stirring at 40 °C for 12 h, 1 mol / L HCl (205 mL, 205 mmol) was added at 0 °C, and all was concentrated in vacuum. The residue was dissolved in 200 mL ethanol and 200 mL toluene, which was then concentrated. The residue was diluted with dry ethanol (200 mL), filtered, and the filtrate was concentrated under reduced pressure. Methyl tert-butyl ether (100 mL) was added to the residue, and the precipitate was collected by filtration, washed with methyl tert-butyl ether (50 mL), and dried to give fragment 2 (2.0 g, 2.87 mmol, 43.62% yield, 88% purity), as a pale yellow solid. MS m / z (ESI): 613 [M+H] + .

[0100] Example 5 Synthesis of Compound 3A TIFF2024540264000016.tif44170

[0101] Synthesis Route: TIFF2024540264000017.tif39170

[0102] Step 1: Synthesis of compound 3A-1: Fragment 2 (700 mg, 1.14 mmol, 1 eq), 3-difluoromethoxy-2-fluoroaniline (364.31 mg, 2.06 mmol, 1.8 eq) in ACN (50 mL) solution was added with T3P (1.82 g, 2.86 mmol, 1.70 mL, 50% purity, 2.5 eq), Et3N (346.88 mg, 3.43 mmol, 477.14 μL, 3 eq) and stirred at 40 °C for 2 h. At 0 °C, the pH was adjusted to 5-6 with sodium carbonate solution, diluted with 100.0 mL of water, extracted with ethyl acetate (100 mL × 3), and concentrated to give compound 3A-1 (300 mg, crude product), which was used directly in the next step without purification. MS m / z (ESI): 772 [M+H] + .

[0103] Step 2: Synthesis of compound 3A: To a solution of compound 3A-1 (300 mg, 388 μmol) in methanol (5.00 mL), sodium methoxide (209 mg, 3.88 mmol) was added and stirred at 25° C. for 2 h. LC-MS showed that compound 3A-1 was completely consumed. The reaction mixture was subjected to layer extraction with 10.0 mL of an aqueous ammonium chloride solution and 20.0 mL of an ethyl acetate solution, and the organic phase was concentrated under reduced pressure to obtain a residue. Reverse-phase high-performance liquid chromatography (column: Xtimate C18 150×40 mm×10 μm, mobile phase: [water (NH3H2O+NH4HCO3], B%: 50%-80%, 10 min) was used. The crude product was purified by reverse-phase high-performance liquid chromatography (column: Welch Xtimate C18 150×30 mm×5 μm, mobile phase: [water(TFA)-ACN], B%: 15%-55%, 10 min) to obtain compound 3A (191 mg, 257.95 μmol, yield 28.44%, purity 98%), as a yellow solid. MS m / z (ESI): 726 [M+H] + ; 1 H NMR (400 MHz CD3OD), δ ppm 7.66 - 7.76 (m, 3 H) 7.57 - 7.65 (m, 1 H) 7.43 - 7.52 (m, 2 H) 7.09 - 7.13 (m, 1 H) 6.89 - 6.95 (m, 1 H) 6.69 - 6.76 (m, 1 H) 5.74 (d, J = 16.00 Hz, 1 H) 5.54 (d, J = 16.00 Hz, 1 H) 4.39 - 4.54 (m, 2 H) 3.75 (s, 3 H) 2.70 - 2.80 (m, 6 H).

[0104] Example 6: Synthesis of Compound 4 TIFF2024540264000018.tif43170

[0105] Synthesis Route: TIFF2024540264000019.tif119170

[0106] Step 1: Synthesis of compound 4-2: To a suspension of SM5 (21.0 g, 88.5 mmol) in anhydrous toluene (100 mL) was added sulfuryl chloride (15.5 g, 115 mmol, 11.5 mL), then stirred at 85 °C for 12 h and at 100 °C for 4 h. LCMS and TLC (Petroleum ether: EtOAc = 5:1, Rf = 0.31) showed that the raw material was almost consumed. The mixture was cooled to 25 °C and quenched with ice water (50.0 mL). The organic layer was separated and the aqueous layer was extracted with toluene (100 mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to give compound 4-2 (23.0 g, 69.4 mmol, 78.4% yield, 82% purity) as a yellow adhesive oil, which did not need further purification and was used directly in the next step. 1 H NMR (400 MHz CDCl3), δppm 8.35 (d, J = 8.8 Hz, 2H), 8.17 (d, J = 8.8 Hz, 2H), 5.56 (s, 1H), 4.34 - 4.28 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H).

[0107] Step 2: Synthesis of compound 4-3: Solution 1: At 0°C, NaH (3.39 g, 84.6 mmol, 60% purity) was added to a solution of tert-butyl 2-cyanoacetate (11.9 g, 84.6 mmol, 12.1 mL) in THF (120 mL) and stirred at 0-25°C for 30 min. Fresh solution 1 was added dropwise to a solution of compound 4-2 (23.0 g, 84.6 mmol) in THF (120 mL), followed by stirring at 25°C for 16 h and 70°C for 24 h. LCMS showed that the starting material was completely consumed. The mixture was stripped of solvent under reduced pressure. The mixture was purified by silica gel column chromatography. Compound 4-3 (18.5 g, 42.7 mmol, 50.5% yield, 87.0% purity) was obtained as an orange solid. MS m / z (ESI): 377 [M+H] + ; 1H NMR (400 MHz CDCl3), δ8.20 (d, J = 9.2 Hz, 2H), 7.63 (d, J = 9.2 Hz, 2H), 5.76 (br.s, 2H), 4.43 - 4.38 (m, 2H), 1.53 (s, 9H), 1.39 (t, J= 7.2Hz, 3H).

[0108] Step 3: Synthesis of compound 4-4: To a solution of compound 4-3 (5.00 g, 13.3 mmol) and Et3N (4.03 g, 39.8 mmol, 5.55 mL) in THF (100 mL) was added ClCO2Et (1.85 g, 17.0 mmol, 1.62 mL) and stirred at 25 °C for 16 h. Another ClCO2Et (1.69 g, 15.5 mmol, 1.48 mL) was added and stirred at 25 °C for 4 h. The solvent was removed under reduced pressure, the residue was dissolved in 50 mL of methanol, K2CO3 (2.75 g, 19.9 mmol) was added and stirred at 50 °C for 16 h. LCMS showed that the starting material was completely consumed. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (150 mL × 3), the organic layer was washed with water (150 mL), brine (100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 4-4 (4.20 g, 8.71 mmol, yield 65.5%, purity 93.0%) as a yellow solid. MS m / z (ESI): 449 [M+H] + ; 1 H NMR (400 MHz CDCl3), δppm 9.02 (br.s, 1H), 8.24 (d, J = 9.2 Hz, 2H), 7.79 (d, J = 8.8 Hz, 2H), 4.44 - 4.38 (m, 2H), 4.33 - 4.30 (m, 2H), 1.55 (s, 9H), 1.41 - 1.35 (m, 6H).

[0109] Step 4: Synthesis of compounds 4-5: To a solution of compound 4-4 (4.50 g, 10.0 mmol) in DMF (50.0 mL), K2CO3 (1.53 g, 11.04 mmol) and KI (1.83 g, 11.0 mmol) were added, followed by 2,6-difluorobenzyl chloride (1.96 g, 12.0 mmol), and stirred at 25 °C for 3 h. LCMS showed that the starting material was already completely consumed. The mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), the organic layer was washed with fresh water (50 mL x 2), dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography. (petroleum ether: EtOAc = 10: 1, Rf = 0.46), compound 4-5 (4.90 g, 8.14 mmol, yield 81.1%, purity 95.5%) was obtained as a yellow oil. MS m / z(ESI):575[M+H] + ; 1 H NMR (400 MHz CDCl3), δppm 8.23 ​​(d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.27 - 7.24 (m, 1H), 6.87 (t, J = 8.0 Hz, 2H), 5.00 (s, 2H), 4.42 - 4.37 (m, 2H), 4.25 - 4.20 (m, 2H), 1.49 (s, 9H), 1.36 (t, J = 7.2 Hz, 3H), 1.25 - 1.23 (m, 3H).

[0110] Step 5: Synthesis of compounds 4-6: To a solution of compound 4-5 (4.90 g, 8.53 mmol) in CH2Cl2 (25.0 mL), TFA (9.24 g, 81.0 mmol, 6.00 mL) was added and stirred at 25 °C for 3 h. LCMS showed that the starting material was already completely consumed. The mixture was removed from the solvent under reduced pressure. The residue was dissolved in 50 mL of CH2Cl2, and the solvent was further removed and the above step was repeated three times to give compound 4-6 (5.20 g, 8.22 mmol, 96.4% yield, TFA) as a brown oil, which was used directly in the next step without purification. MS m / z (ESI): 519 [M+H] + ;1 H NMR (400 MHz CDCl3), δppm 8.28 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7.31 - 7.25 (m, 1H), 6.87 (t, J = 8.0 Hz, 2H), 5.02 (s, 2H), 4.41 - 4.35 (m, 2H), 4.26 - 4.23 (m, 2H), 1.26 (t, J = 7.2 Hz, 6H).

[0111] Step 6: Synthesis of compounds 4-7: To a solution of compound 4-6 (4.00 g, 7.72 mmol) and 3-amino-6-methoxypyridazine (2.00 g, 15.9 mmol) in tetrahydrofuran (80.0 mL), N-methylimidazole (2.53 g, 30.8 mmol, 2.46 mL) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (4.33 g, 15.4 mmol) were added, and then the mixture was stirred at 25 °C for 16 h. LCMS showed that the starting material was completely consumed. The solvent in the mixture was removed by reduced pressure. The residue was purified by silica gel (petroleum ether: ethyl acetate = 2: 1 to 0: 1) column chromatography to give compound 4-7 (2.90 g, 4.27 mmol, yield 55.3%, purity 92.0%), as a yellow oil. MS m / z (ESI): 626 [M + H] + ; 1 H NMR (400 MHz CDCl3), δppm 10.76 (br.s, 1H), 8.49 (d, J = 9.6 Hz, 1H), 8.28 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H ), 7.25 - 7.23 (m, 1H), 7.09 (d, J = 9.2 Hz, 1H), 6.84 (t, J = 8.0 Hz, 2H), 5.04 (s, 2H), 4.35 - 4.29 (m, 4H), 4.13 (s, 3H), 1.31 - 1.18 (m, 6H).

[0112] Step 7: Synthesis of compounds 4-8: To a solution of compound 4-7 (2.50 g, 4.00 mmol) in THF (20 mL) and EtOH (20 mL), LiBH4 (435 mg, 19.9 mmol) was added and stirred at 0 °C for 1 h, then at 0-25 °C for 3 h. LCMS showed that the starting material was completely consumed. The mixture was poured into aq. NH4Cl solution (150 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with brine (50.0 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to give compound 4-8 (2.30 g, 3.19 mmol, 79.9% yield, 81.0% purity) as a yellow solid, which was used directly in the next step without purification. MS m / z (ESI): 584 [M+H] + .

[0113] Step 8: Synthesis of compounds 4-9: At 0°C, SOCl2 (905 mg, 7.61 mmol, 552 μL) was added to a solution of compound 4-8 (2.22 g, 3.80 mmol) in CH2Cl2 (50.0 mL) and stirred at 0-25°C for 3 h. LCMS showed that the starting material had already been completely consumed. The mixture was evaporated under reduced pressure to give compound 4-9 (2.30 g, crude), a yellow solid, which was used directly in the next step without purification. MS m / z (ESI): 602 [M+H] + .

[0114] Step 9: Synthesis of compounds 4-10: To a solution of compound 4-9 (2.30 g, 3.82 mmol) in CH2Cl2 (50.0 mL), Et3N (3.87 g, 38.2 mmol, 5.32 mL) and dimethylamine hydrochloride (1.56 g, 19.1 mmol) were added and stirred at 25 °C for 16 h. LCMS showed that the starting material was already completely consumed. The mixture was diluted with CH2Cl2 (100 mL), washed with water (50.0 mL × 2), and the aqueous layer was extracted with CH2Cl2 (50.0 mL). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. Purification by silica gel column chromatography gave compound 4-10 (1.40 g, 2.13 mmol, yield 55.8%, purity 93.0%) as a yellow solid. MS m / z (ESI): 611 [M+H] + .

[0115] Step 10: Synthesis of compounds 4-11: To a solution of compound 4-10 (210 mg, 344 μmol) in anhydrous methanol (20 mL), CH3ONa (186 mg, 3.44 mmol) was added and stirred at 25 °C for 16 h. LCMS showed that the starting material was completely consumed, and the expected product was observed. The mixture of four batches was mixed, poured into aq. NH4Cl solution (150 mL), extracted with ethyl acetate (150 mL x 3), washed with water (100 mL) and brine (100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. Purification by silica gel column chromatography gave compound 4-11 (530 mg, 884 μmol, yield 64.3%, purity 94.2%) as a yellow solid. MS m / z (ESI): 565 [M+H] + ; 1H NMR (400 MHz CDCl3), δppm 8.35 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 9.2 Hz, 2H), 7.42 - 7.35 (m, 2H), 7.17 (d, J = 9.2 Hz, 1H), 6.99 - 6.95 (m, 2H), 5.45 (s, 2H), 4.19 (s, 3H), 4.00 - 3.73 (m, 2H), 2.48 (s, 6H).

[0116] Step 11: Synthesis of compounds 4-12: Under N2 protection, Pd / C (50.0 mg, 86.0 μmol, 10% purity) was added to a solution of compound 4-11 (105 mg, 172 μmol) in EtOH (5.00 mL) and THF (5.00 mL), then degassed under vacuum and replaced with H2 three times. The mixture was stirred at 25 °C for 16 h under H2 (15 PSI) atmosphere. LCMS showed that the starting material was already completely consumed. The mixture was filtered through a pad of diatomaceous earth, and the filter cake was washed with 30 mL of ethanol (EtOH). The filtrate was removed with solvent under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH = 10:1, Rf = 0.31) to give compound 4-12 (67.0 mg, 100 μmol, 58.3% yield, 87.0% purity), as a brown oil. MS m / z (ESI): 535 [M+H] + .

[0117] Step 12: Synthesis of compound 4: Compound 4-12 (50.0 mg, 93.5 μmol) was added to CHCl (5 mL), DIPEA (105 mg, 812 μmol, 141 μL) and CDI (60.6 mg, 374 μmol) were added, and the mixture was stirred at 25°C for 16 h. DIPEA (120 mg, 935 μmol, 163 μL) and CDI (60.0 mg, 370 μmol) were further added, and the mixture was stirred at 25°C for 2 h. CDI (151 mg, 935 μmol) was added, and the mixture was stirred at 25°C for 2 h. CDI (151 mg, 935 μmol) was added, and the mixture was stirred at 25°C for 2 h. Methoxyamine hydrochloride (78.1 mg, 935 μmol) was added, and the mixture was stirred at 25°C for 2 h. LCMS showed that the starting material was completely consumed. The mixture was diluted with ethyl acetate (50 mL) and washed with water (20 mL×2) and brine (20 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Purification by silica gel column chromatography gave compound 4 (35.0 mg, 52.4 μmol, yield 56.0%, purity 91.0%) as an off-white solid. MS m / z(ESI): 608 [M+H] + ; 1 H NMR (400 MHz CD3OD), δppm 7.73 - 7.63 (m, 5H), 7.40 - 7.36 (m, 2H), 7.05 - 7.01 (m, 3H), 5.46 (s, 2H), 4.16 (s, 3H), 3.75 - 3.73 (m, 5H), 2.29 (s, 6H).

[0118] Example 7 Synthesis of Compound 5 TIFF2024540264000020.tif48170

[0119] Synthesis Route: TIFF2024540264000021.tif36170

[0120] Step 1: Synthesis of compound 5-1: Fragment 2 (700 mg, 1.14 mmol, 1 eq), 3-amino-6-methoxypyridazine (714.91 mg, 5.71 mmol, 5 eq) were dissolved in DMF (10 mL) solution, T3P (5.82 g, 9.14 mmol, 5.44 mL, 50% purity, 8 eq) and DIEA (2.22 g, 17.14 mmol, 2.99 mL, 15 eq) were added, and the mixture was stirred at 25 °C for 2 h. At 0 °C, the pH was adjusted to 5-6 with sodium carbonate solution, further diluted with 100.0 mL of water, extracted with ethyl acetate (100 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was concentrated under reduced pressure to give compound 5-1 (650 mg, crude product), a yellow oil. MS m / z (ESI): 720 [M + H] + .

[0121] Step 2: Synthesis of compound 5: Compound 5-1 (650 mg, 903.15 μmol, 1 eq) was dissolved in MeOH (20 mL), NaOMe (487.91 mg, 9.03 mmol, 10 eq) was added, and the mixture was stirred at 25 °C for 2 h. At 0 °C, the pH was adjusted to 5-6 with sodium carbonate solution, further diluted with 100.0 mL of water, extracted with ethyl acetate (100 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (column: Xtimate C18 150 × 40 mm × 10 μm, mobile phase: [water (NH3H2O ​​+ NH4HCO3) -ACN], B%: 40% ~ 70%, 10 min). Compound 5 (137 mg, 199.31 μmol, yield 22.07%, purity 98%) was obtained as a yellow solid. MS m / z(ESI):674[M+H] + ; 1 H NMR (400 MHz CD3OD), δppm 7.55 - 7.72 (m, 5 H) 7.34 - 7.48 (m, 4 H) 4.17 (s, 3 H) 3.74 (s, 1 H) 3.64 - 3.87 (m, 1 H) 3.60 - 4.00 (m, 1 H) 2.08 - 2.24 (m, 6H).

[0122] Example 8: Synthesis of Compound 6 TIFF2024540264000022.tif41170

[0123] Synthesis Route: TIFF2024540264000023.tif122170

[0124] Step 1: Synthesis of compound 6-1: To a solution of SM6 (5.00 g, 38.6 mmol) in dioxane (100 mL), DMAP (94.3 mg, 771 μmol) and di-tert-butyl dicarbonate (12.6 g, 57.8 mmol, 13.3 mL) were added and stirred at 80 °C for 2 h. LC-MS showed that the starting material b1 was completely consumed, so the reaction mixture was extracted with ethyl acetate to obtain the mono- and di-protected amines. The mono- and di-protected amines were dissolved in methanol (100 mL) and potassium carbonate (1.26 g, 9.10 mmol) was added. The mixture was stirred at 25 °C until the di-protected amine could not be observed by LC-MS. The reaction mixture was poured into water (100.0 mL) and filtered to obtain compound 6-1 (4.60 g, 18.2 mmol, 52.0% yield, 91% purity), a yellow solid. MS m / z (ESI): 230 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 8.28 - 8.25 (d, J = 9.2 Hz, 1H), 7.99 (br s, 1H), 7.47 - 7.45 (d, J= 9.6 Hz, 1H), 1.54 (s, 9H).

[0125] Step 2: Synthesis of compound 6-2: Compound 6-1 (4.60 g, 20.0 mmol) was added to a solution of THF (300 mL), and NaH (961 mg, 24.0 mmol, 60.0% purity) was added at 0 °C, stirred at 0 °C for 20 min, and then MeI (3.70 g, 26.0 mmol, 1.62 mL) was added at 0 °C. The resulting mixture was stirred at 25 °C for 40 min. LC-MS showed that compound 6-1 was completely consumed. The reaction mixture was quenched with 100 mL of water at 0 °C, extracted with ethyl acetate (150 mL × 3), and the combined organic layers were dried with [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1) to give compound 6-2 (3.00 g, 12.3 mmol, 61.4% yield) as a white solid. MS m / z (ESI): 244 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 8.13 - 8.11 (d, J = 9.2 Hz, 1H), 7.39 - 7.37 (d, J = 9.2 Hz, 1H), 3.55 (s, 3H), 1.55 (s, 9H).

[0126] Step 3: Synthesis of compound 6-3: Under nitrogen protection, to a solution of compound 6-2 (3.00 g, 12.3 mmol), benzophenone imine (2.68 g, 14.77 mmol, 2.48 mL) in toluene (30.0 mL), BINAP (1.53 g, 2.46 mmol), Cs2CO3 (8.02 g, 24.6 mmol), Pd2(dba)3 (1.13 g, 1.23 mmol) were added, and the mixture was stirred at 110 °C for 16 h under nitrogen protection. LCMS showed that the starting material was completely consumed. The solvent was removed under reduced pressure to give compound 6-3 (5.00 g, crude), a yellow oil. MS m / z (ESI): 389 [M+H] + .

[0127] Step 4: Synthesis of compound 6-4: Compound 6-3 (5.00 g, 4.38 mmol, purity 34.0%) was dissolved in THF (100 mL), HCl (1 M, 10.0 mL) was added, and the mixture was stirred at 25 °C for 30 min. LC-MS showed that compound 6-3 was completely consumed, so the reaction mixture was added with sodium carbonate solution (5.00 mL) and extracted with ethyl acetate (10.0 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give compound 6-4 (800 mg, 3.57 mmol, yield 81.5%) as a yellow solid. MS m / z (ESI): 244 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 7.33 - 7.31 (d, J = 9.2 Hz, 1H), 6.76 - 6.74 (d, J = 2.4 Hz, 1H), 6.26 (s, 2H), 3.19 (s, 2H), 1.39 (s, 7H).

[0128] Step 5: Synthesis of compound 6-5: Compound 6-4 (500 mg, 2.23 mmol) was dissolved in 4 M HCl / 1,4-dioxane (2.23 mmol, 1 mL) solution and stirred at 25 °C for 2 h. LC-MS showed that compound 6-4 was completely consumed. The reaction was concentrated under reduced pressure to give compound 6-5 (276 mg, 2.22 mmol, 99.7% yield), which was a white solid. MS m / z (ESI): 125 [M+H] + .

[0129] Step 6: Synthesis of compound 6-6: To a solution of fragment 1 (600 mg, 1.07 mmol), compound 6-5 (264 mg, 2.13 mmol) in ACN (10.0 mL), T3P (2.04 g, 3.20 mmol, 1.90 mL, purity 50.0%) and Et3N (1.08 g, 10.6 mmol, 1.48 mL) were added and stirred at 40 °C for 2 h. LC-MS showed that fragment 1 was completely consumed. At 0 °C, the pH value was adjusted to 5-6 with sodium carbonate solution, then diluted with 20.0 mL of water and extracted with ethyl acetate (30.0 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give yellow solid compound 6-6. MS m / z (ESI): 769 [M+H] + .

[0130] Step 7: Synthesis of compound 6: Sodium methoxide (484 mg, 8.97 mmol) was added to a solution of compound 6-6 (600 mg, 897 μmol) in methanol (5.00 mL) and stirred at 25 °C for 2 h. LC-MS showed that compound 6-6 was completely consumed. The reaction mixture was subjected to layer extraction with 10.0 mL of aqueous ammonium chloride solution and 20.0 mL of ethyl acetate solution, and the organic phase was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH = 20 / 1 to 10 / 1) to obtain compound 6 (200 mg, 321 μmol, yield 35.8%) as a white solid. MS m / z (ESI): 623 [M+H] + ; 1 H NMR (400 MHz CD3OD), δ ppm 7.75 - 7.73 (d, J = 8.4 Hz, 2H), 7.46 - 7.41 (m, 3H), 7.36 - 7.38 (d, J= 9.2 Hz, 1H), 7.08 - 7.02(m, 3H), 5.47 - 5.45 (d, J = 10.4 Hz, 2H), 4.49 - 4.45 (br d, J = 14.8 Hz, 2H), 3.75 (s, 3H), 3.02 (s, 3H), 2.75 (s, 6H).

[0131] Example 9: Synthesis of Compound 7 TIFF2024540264000024.tif40170

[0132] Synthesis Route: TIFF2024540264000025.tif122170

[0133] Step 1: Synthesis of compound 7-1: At 0° C., PPh3 (19.2 g, 73.5 mmol) was added to SM7 (10.0 g, 61.3 mmol), 2,2-difluoroethanol (5.03 g, 61.3 mmol), and tetrahydrofuran (100 mL), and the mixture was stirred at 25° C. for 20 h. LC-MS showed that SM7 was completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=4 / 1) to give compound 7-1 (4.00 g, 17.6 mmol, 28.7%) as a white solid. MS m / z(ESI): 228[M+H] + ; 1 H NMR (400 MHz CDCl3), δppm 7.89 - 7.86 (m, 1H), 7.80 - 7.78 (m, 2H), 6.38 - 6.09 (m, 1H), 4.42 - 4.35 (m, 2H).

[0134] Step 2: Synthesis of compound 7-2: Compound 7-1 (4.00 g, 17.6 mmol), NH2NH2H2O (2.01 g, 39.3 mmol, 1.95 mL, 98.0% purity) were reacted in CHCl2 (100 mL). LC-MS showed that compound 7-1 was completely consumed. The reaction mixture was filtered, the filtrate was washed with 10.0 mL of water, and the combined organic layer was adjusted to pH 1 with HCl / 1,4-dioxane 4 M (5.00 mL), filtered, and compound 7-2 (2.00 g, 14.9 mmol, 85.0% yield) was obtained as a white solid. MS m / z (ESI): 134 [M+H] + ; 1H NMR (400 MHz DMSO-d6), δppm 11.3 (s, 2H), 6.51- 6.22 (m, 1H), 4.36 - 4.28 (t, J = 29.6 Hz, 1H).

[0135] Step 3: Synthesis of compound 7-3: NaOH (3.29 g, 82.1 mmol) was added to H2O (40.0 mL) to produce 2N NaOH. The solution was added to a solution of fragment 1-4 (9.00 g, 16.4 mmol) in EtOH (243 mL). The mixture was stirred at 60 °C for 6 h. LC-MS showed that fragment 1-4 was completely consumed, and 1 N HCl (81.0 mL) was added at 0 °C and concentrated in vacuum. The residue was dissolved in diethyl ether (100 mL) and toluene (100 mL), and all were concentrated in vacuum. The residue was diluted with dry ethanol (100 mL) and then filtered, the filtrate was concentrated in vacuum, and methyl tert-butyl ether (100 mL) was added to the residue and concentrated in vacuum to give compound 7-3 (8.00 g, 13.8 mmol, 84.3% yield), a yellow solid. MS m / z (ESI): 520 [M+H] + .

[0136] Step 4: Synthesis of compound 7-4: Compound 7-3 (7.00 g, 13.4 mmol), 3-amino-6-methoxypyridazine (3.37 g, 26.9 mmol) in ACN (100 mL), T3P (25.7 g, 40.4 mmol, 24.0 mL, purity 50.0%), Et3N (3.41 g, 33.6 mmol, 4.69 mL) were added and stirred at 40 °C for 2 h. LC-MS showed that compound 7-3 was completely consumed. After adjusting the pH to 5-6 with sodium carbonate solution at 0 °C, it was then diluted with 100 mL of water and extracted with ethyl acetate (150 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 7-4 (7.70 g, crude product), a yellow solid. MS m / z (ESI): 627 [M+H] + .

[0137] Step 5: Synthesis of compound 7-5: To a solution of compound 7-4 (7.20 g, 11.4 mmol) in methanol (200 mL) was added sodium methoxide (6.21 g, 114.9 mmol) and the reaction mixture was stirred at 25 °C for 2 h. LC-MS showed that compound 7-4 was completely consumed. The reaction mixture was stratified between aqueous ammonium chloride (10.0 mL) and ethyl acetate (200 mL). The organic phase was concentrated under reduced pressure to give compound 7-5 (4.30 g, crude), a yellow solid. MS m / z (ESI): 581 [M+H] + ; 1 H NMR (400 MHz DMSO-d6), δppm 8.34 - 8.32 ( d, J = 8.40 Hz, 2H), 8.00 - 07.97 ( d, J = 8.80 Hz, 2H), 7.76 - 7.74 ( d, J = 9.20 Hz, 2H),7.51 - 7.44 (m, 1H), 7.17 - 7.13 (t, J= 16.4 Hz, 2H), 5.43 - 5.21 (m, 2H), 4.09 (s, 3H), 3.73 - 3.66 (d, J = 27.2 Hz, 2H), 2.08 (s, 6H).

[0138] Step 6: Synthesis of compound 7-6: Compound 7-5 (4.70 g, 8.10 mmol) was dissolved in EtOH (500 mL), Pd / C (800 mg, 1.62 mmol) was added, and the mixture was stirred at 25 °C for 1 h. LC-MS showed that compound 7-5 was completely consumed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, dichloromethane:MeOH = 10 / 1) to give compound 7-6 (2.90 g, 5.27 mmol, yield 65.0%) as a white solid. MS m / z (ESI): 551 [M + H] + ; 1H NMR (400 MHz CD3OD), δ7.66 - 7.63 (m, 1H), 7.41 - 7.36 (m, 2H), 7.17 - 7.15 (m, 2H), 7.03 - 6.99 (m, 2H), 6.75 - 6.73 (m, 2H), 5.38 (s, 2H), 4.16 (s, 3H), 3.91 - 3.83 (m, 2H), 2.04 (s, 6H).

[0139] Step 7: Synthesis of compound 7: To a solution of compound 7-6 (200 mg, 363 μmol) in dichloromethane (5.00 mL), DIPEA (94.8 mg, 733 μmol, 127 μL) and CDI (117 mg, 726 μmol) were added. After stirring at 25 °C for 14 h, the mixture was cooled to 0 °C. DIPEA (478 mg, 3.71 mmol, 645 μL) and compound 7-2 (485 mg, 3.63 mmol) were added to the mixture and stirred at 25 °C for 2 h. LC-MS showed that compound 7-6 was completely consumed, and the reaction mixture was added with sodium carbonate solution (5.00 mL) and extracted with ethyl acetate (10.0 mL × 3), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane:MeOH=10 / 1) to give the crude product, which was further purified by preparative TLC method (SiO2, dichloromethane:MeOH=10 / 1) to give compound 7 (10.0 mg, 14.8 μmol, 4.09% yield), as a yellow solid. MS m / z(ESI): 674[M+H] + ; 1 H NMR (400 MHz CD3OD), δppm 7.67 - 7.63 (m, 3H), 7.43 - 7.37 (m, 3H), 7.03 - 6.99 (t, J = 16.4 Hz, 2H), 6.29 - 6.02 (m, 1H), 3.46 - 3.35 (m, 1H), 5.39 (s, 2H), 4.16 (s, 3H), 4.14 - 4.07 (m, 2H), 2.00 (s, 6H).

[0140] Example 10: Synthesis of Compound 2A TIFF2024540264000026.tif49170

[0141] Synthesis Route: TIFF2024540264000027.tif38170

[0142] Step 1: Synthesis of compound 2A: To a solution of compound 7-6 (0.10 g, 182 μmol, 1.00 eq) in DMF (5 mL), Et3N (110 mg, 1.09 mmol, 152 μL, 6.00 eq) was added and stirred at 0 °C for 30 min. Then, ethyl isocyanate (103 mg, 1.99 mmol, 403 μL, 28.0 eq) was added at 0 °C. The mixture was stirred at 50 °C for 17 h under N2 atmosphere. Et3N (55.1 mg, 545 μmol, 75.8 μL, 3.00 eq) and ethyl isocyanate (258 mg, 3.63 mmol, 288 μL, 20.00 eq) were added and stirred at 50 °C for 5 h. Et3N (55.1 mg, 545 μmol, 75.8 μL, 3.00 eq) and isocyanoethane (387 mg, 5.45 mmol, 431 μL, 30.0 eq) were added and stirred at 50 °C for 5 h. LCMS showed that compound 7-6 was completely consumed. The mixture was poured into water (20 mL), extracted with ethyl acetate (15 mL x 3), washed with brine (10 mL x 2), dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by silica gel (dichloromethane / methanol = 94 / 6) column chromatography. The obtained compound 2A (52.3 mg, 81.6 μmol, yield 44.9%, purity 97.0%) was obtained as a white solid. MS m / z (ESI): 622 [M+H] + ; 1H NMR (400 MHz CD3OD), δppm 8.32 (s, 1 H), 7.67 (d, J = 9.13 Hz, 1 H), 7.40 (d, J = 8.50 Hz, 2 H), 7.27 - 7.32 (m, 1 H), 7.24 (d, J = 9.13 Hz, 1 H), 6.95 (d, J = 8.38 Hz, 2 H), 6.83 - 6.91 (m, 2 H), 6.02 (br t, J= 5.32 Hz, 1 H), 5.08 - 5.36 (m, 2 H), 4.19 - 4.19 (m, 1 H), 4.19 (s, 2 H), 3.88 - 4.09 (m, 1 H), 3.30 (s, 2 H), 2.19 (s, 6 H), 1.16 (t, J = 7.19 Hz, 3 H). 19 F NMR: (400 MHz CDCl3) δ -114.827 ppm.

[0143] Example 11: Synthesis of Fragment 3 TIFF2024540264000028.tif41170

[0144] Synthesis Route: TIFF2024540264000029.tif143170

[0145] Step 1: Synthesis of fragment 3-1: SM8 (10.0 g, 86.9 mmol) in THF (10.0 mL) at -70 °C was added with a solution of LDA (2 M, 43.5 mL) (100 mL). The mixture was stirred at -70 °C for 30 h, then methyl formate solution (10.4 g, 174 mmol, 10.5 mL, 2 eq) was added. The mixture was stirred at -70 °C for 1 h, then at 20 °C for 1 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf = 0.43) showed complete reaction. After cooling to 25 °C, the mixture was poured into aq. NaHCO3 (100 mL), extracted with ethyl acetate (50.0 mL × 3), and concentrated under reduced pressure to give fragment 3-1 (8.00 g, 55.9 mmol, 64.3%) as a yellow solid. 1H NMR (400 MHz CDCl3), δ ppm 8.55 (s, 2 H), 10.41 (s, 1 H).

[0146] Step 2: Synthesis of fragment 3-2: To a solution of fragment 3-1 (8.00 g, 55.9 mmol, 1 eq) in MeOH (100 mL) was added a solution of NaBH4 (3.17 g, 83.9 mmol, 1.5 eq) in MeOH (10 mL) at 0 °C. The mixture was stirred at 20 °C for 2 h. LCMS showed the reaction was complete. The reaction was quenched by adding water (50 mL) and concentrated under reduced pressure to remove methanol. The residue was extracted with ethyl acetate (100 mL × 3), and the combined organic phase was washed with brine (30.0 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. Pulping with petroleum ether:ethyl acetate = 10:1 (100 mL) for 1 h at 25 °C gave fragment 3-2 (6.21 g, 42.8 mmol, 77.6% yield), a yellow solid. MS m / z (ESI): 146 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 2.64 (br.s, 1H), 4.84 (s, 2H), 8.35 (s, 2H).

[0147] Step 3: Synthesis of fragment 3-3: Compound fragment 3-2 (6.21 g, 42.8 mmol, 1 eq) was dissolved in CH2Cl2 (125 mL) under N2 condition. DIPEA (8.30 g, 64.2 mmol, 11.2 mL, 1.5 eq) and MsCl (6.00 g, 52.4 mmol, 4.05 mL, 1.22 eq) were added, respectively. The mixture was heated to 25 °C and stirred at 25 °C for 16 h. LC-MS showed the reaction was complete. 50 mL of methylbenzene was added twice and concentrated again. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 3 / 1) to give fragment 3-3 (2.46 g, 15.0 mmol, 35.1%) as a pale yellow liquid. MS m / z (ESI): 164 [M+H] + ;1 H NMR (400 MHz CDCl3), δ ppm 4.62 (s, 2H), 8.38 (s, 2H).

[0148] Step 4: Synthesis of fragment 3-4: To a solution of compound 1-1 (5.00 g, 13.2 mmol, 1 eq) in DMF (160 mL) was added KI (2.48 g, 14.9 mmol, 1.13 eq) and K2CO3 (2.06 g, 14.9 mmol, 1.13 eq). Then, to the mixture was added a solution of fragment 3-3 (2.45 g, 14.9 mmol, 1.13 eq) in DMF (12 mL). LC-MS showed that the reaction was complete. The resulting precipitate was filtered and the filtrate was concentrated in vacuum. The residue was diluted with ethyl acetate (70 mL) and water (70 mL), extracted with ethyl acetate (70 mL x 2), washed with water (70 mL) and brine (70 mL), dried over Na2SO4, and concentrated in vacuum. Methyl tert-butyl ether (35 mL) was added to the residue, and the precipitate was collected by filtration and washed with methyl tert-butyl ether (10.0 mL) to give fragment 3-4 (6.35 g, 12.5 mmol, 95.1% yield) as a pale yellow solid. MS m / z (ESI): 506 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 1.19 - 1.37 (m, 6 H), 2.41 (s, 3 H), 4.13 - 4.33 (m, 4 H), 5.00 (s, 2 H), 7.54 (d, J = 8.80 Hz, 2 H), 8.28 (d, J = 8.80Hz, 2H), 8.34(s, 2H).

[0149] Step 5: Synthesis of fragment 3-5: Fragment 3-4 (6.35 g, 12.56 mmol, 1 eq), NBS (2.79 g, 15.70 mmol, 1.25 eq) and AIBN (206.28 mg, 1.26 mmol, 0.1 eq) were dissolved in ethyl acetate (75 mL) and reacted at 80 °C for 2 h. To the mixture was added NBS (447 mg, 2.51 mmol, 0.2 eq) and AIBN (20.6 mg, 125.6 μmol, 0.01 eq) and heated at 80 °C for 6 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with ethyl acetate (50 mL) and water (50 mL), extracted with ethyl acetate (30 mL x 2), washed with water (40 mL) and brine (40 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 8 / 1) to give fragment 3-5 (4.63 g, 7.92 mmol, 63.07%) as a pale yellow solid. MS m / z (ESI): 584, 586 [M+H] + .

[0150] Step 6: Synthesis of fragment 3-6: At 25 °C, fragment 3-5 (4.63 g, 7.92 mmol, 1 eq), dimethylamine (1.94 g, 23.8 mmol, 2.18 mL, 3 eq, HCl) and DMF (20.1 mL) were added to a 100 mL one-neck round-bottom flask. Then triethylamine (3.21 g, 31.7 mmol, 4.41 mL, 4 eq) was added and stirring was continued for 2 h. LC-MS showed the reaction was complete. The reaction was stopped, water (60 mL) was added, extracted with ethyl acetate (60 mL × 3), the liquid was separated, the organic phase was collected and rotary dried under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 4) to give fragment 3-6 (3.05 g, 5.56 mmol, 70.2% yield), a pale yellow solid. MS m / z (ESI): 549 [M+H] + ; 1H NMR (400 MHz CDCl3), δ ppm 1.10 - 1.25 (m, 3 H), 1.31 (t, J= 7.20 Hz, 3 H), 2.08 (s, 6 H), 3.55 (s, 2 H), 4.14 - 4.30 (m, 4 H), 5.05 (s, 2 H), 7.66 (d, J = 7.66 Hz, 2 H), 8.27 (d, J = 8.80 Hz, 2 H), 8.33 (s, 2 H).

[0151] Step 7: Synthesis of fragments 3-7: Fragment 3-6 (3.05 g, 5.56 mmol, 1 eq) and HCl / 1,4-dioxane (4 M, 2.78 mL, 2 eq) in EtOH (84.0 mL) was added with Pd / C (0.99 g, 5.56 mmol, 10% purity, 1.00 eq) and hydrogenated at 25 °C and 15 psi hydrogen gas pressure for 1 h. LC-MS showed the reaction was complete. It was filtered through diatomaceous earth and the filtrate was diluted with saturated aqueous NaHCO3 (25 mL). The filtrate was concentrated under reduced pressure, ethyl acetate (50 mL) and water (50 mL) were added, and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give fragment 3-7 (2.74 g, 95.0% yield), a pale yellow oil, which was used directly in the next step without purification. MS m / z(ESI):519[M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 1.11 - 1.24 (m, 3 H), 1.31 (t, J= 7.20 Hz, 1 H), 1.28 - 1.34 (m, 3 H), 2.02 - 2.06 (m, 6 H), 3.43 - 3.60 (m, 2 H), 3.75 - 3.87 (m, 2 H), 4.15 - 4.31 (m, 4 H), 4.98 - 5.08 (m, 2 H), 6.66 - 6.72 (m, 2 H), 7.13 - 7.20 (m, 2 H), 8.27 - 8.33 (m, 2 H).

[0152] Step 8: Synthesis of fragments 3-8: To a solution of fragment 3-7 (2.74 g, 5.28 mmol, 1 eq) in CHCl (70 mL) was added N,N-diisopropylethylamine (2.80 g, 21.6 mmol, 3.77 mL, 4.1 eq) and CDI (3.43 g, 21.1 mmol, 4 eq). The mixture was stirred at 25 °C for 13 h. The mixture was cooled to 0 °C. To the mixture was added methoxyamine hydrochloride (4.42 g, 52.8 mmol, 10 eq, HCl) and N,N-diisopropylethylamine (6.82 g, 52.8 mmol, 9.20 mL, 10 eq) and stirred at 25 °C for 8 h. LC-MS showed the reaction was complete. The reaction was washed with saturated aqueous NaHCO (80 mL). The organic layer was separated, the aqueous layer was extracted with CH2Cl2 (50 mL × 2), and the combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 30 / 1 to 8 / 1) to give fragment 3-8 (2.82 g, 4.77 mmol, 71.57% yield), as a pale yellow oil. MS m / z (ESI): 578 [M+H] + ; 1 H NMR (400 MHz DMSO-d6), δ ppm 1.00 - 1.22 (m, 6 H), 1.93 (s, 6 H), 3.42 (s, 2 H), 3.63 (s, 3 H), 4.07 (q, J = 7.20 Hz, 4 H), 4.97 (s, 2 H), 7.32 (d, J = 7.20 Hz, 2 H), 7.69 (d, J = 8.40 Hz, 2 H), 8.51 (s, 2 H), 9.06 (s, 1 H), 9.62 (s, 1 H).

[0153] Step 9: Synthesis of fragment 3: Sodium hydroxide (953 mg, 23.8 mmol, 5 eq) was added to water (12 mL) to form a 2 M sodium hydroxide solution. 2 M NaOH solution was added to a solution of fragment 3-8 (2.82 g, 4.77 mmol, 1 eq) in EtOH (72 mL). The mixture was stirred at 60 °C for 2 h. LC-MS showed the reaction was complete. 1 mol / L HCl (24 mL) was added at 0 °C and concentrated in vacuum. The residue was dissolved in 50 mL x 3 ethanol and 50 mL x 3 toluene and concentrated in vacuum. The residue was diluted with dry ethanol and then filtered, and the filtrate was concentrated in vacuum. The residue was purified by high-performance liquid chromatography (neutral conditions, column: xate C18 150 × 40 mm × 10 μm, mobile phase: [water(NH4HCO3)-ACN], B%: 10% to 50%, 10 min) to obtain fragment 3 (1.33 g, 2.36 mmol, yield 49.5%) as a pale yellow solid. MS m / z (ESI): 564 [M+H] + ; 1 H NMR (400 MHz DMSO-d6), δ ppm 1.08 (t, J = 6.82 Hz, 3 H), 2.45 (s, 6 H), 3.63 (s, 3 H), 3.95 (s, 2 H), 4.03 (q, J=6.82 Hz, 2 H), 4.95 (s, 2 H), 7.22 (d, J = 8.40 Hz, 2 H), 7.72 (d, J = 8.80 Hz, 2 H), 8.49 (s, 2 H), 9.2 (s, 1 H), 9.64 (s, 1 H).

[0154] Example 12: Synthesis of Compound 8 TIFF2024540264000030.tif41170

[0155] Synthesis Route: TIFF2024540264000031.tif39170

[0156] Step 1: Synthesis of compound 8-1: Fragment 3 (500 mg, 887.20 μmol, 1 eq), 3-difluoromethoxy-2-fluoroaniline (282.86 mg, 1.60 mmol, 1.8 eq) were dissolved in ACN (10 mL), T3P (1.69 g, 2.66 mmol, 1.58 mL, 50% purity, 3 eq), Et3N (224.44 mg, 2.22 mmol, 308.72 μL, 2.5 eq) were added, and the mixture was stirred at 40 °C for 12 h. T3P (1.69 g, 2.66 mmol, 1.58 mL, 50% purity, 3 eq), Et3N (224.44 mg, 2.22 mmol, 308.72 μL, 2.5 eq) were added, and the mixture was stirred at 40 °C for 6 h. The pH was adjusted to 5-6 with saturated sodium carbonate solution at 0°C, further diluted with 100.0 mL of water, extracted with ethyl acetate (100 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was concentrated under reduced pressure to give compound 8-1 (600 mg, crude product), which was a yellow oil. MS m / z (ESI): 723 [M+H] + .

[0157] Step 2: Synthesis of compound 8: Compound 8-1 (600 mg, 830.24 μmol, 1 eq) was dissolved in MeOH (10 mL) and NaOMe (448.53 mg, 8.30 mmol, 10 eq) was added. The mixture was stirred at 25 °C for 2 h. At 0 °C, the pH was adjusted to 5-6 with saturated sodium carbonate solution, further diluted with 100.0 mL of water, extracted with ethyl acetate (100 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. It was purified by column chromatography (SiO2, DCM:methanol = 100 / 1-10 / 1) and further purified by preparative TLC (SiO2, DCM:MeOH = 10:1). Compound 8 (114 mg, 141.88 μmol, yield 17.09%, purity 96%) was obtained as a yellow solid. MS m / z (ESI): 677 [M+H] + ; 1H NMR (400 MHz CD3OD), δ ppm 8.43 (s, 2 H) 7.67 (d, J = 8.00 Hz, 2 H) 7.40 - 7.48 (m, 3 H) 7.25 - 7.39 (m, 2 H) 7.06 - 7.11 (m, 1 H) 6.90 (s, 1 H) 6.72 (s, 1 H) 5.32 - 5.61 (m, 2 H) 4.60 (br s, 1 H) 3.92 - 4.05 (m, 1 H) 3.55 - 3.80 (m, 4 H) 2.06 - 2.22 (m, 6 H).

[0158] Example 13: Synthesis of Compound 8A TIFF2024540264000032.tif38170

[0159] Synthesis Route: TIFF2024540264000033.tif41170

[0160] Step 1: Synthesis of compound 8A-1: To a solution of fragment 3 (500 mg, 887.20 μmol, 1 eq) was added 3-amino-6-methoxypyridazine (555.07 mg, 4.44 mmol, 5 eq), T3P (4.52 g, 7.10 mmol, 4.22 mL, 50% purity, 8 eq) and DIEA (1.72 g, 13.31 mmol, 2.32 mL, 15 eq) in DMF (10 mL). The mixture was stirred at 25 °C for 12 h. At 0 °C, the pH was adjusted to 5-6 with saturated sodium carbonate solution, further diluted with 100.0 mL of water, extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Compound 8A-1 (470 mg, crude product) was obtained as a yellow oil. MS m / z (ESI): 671 [M+H] + .

[0161] Step 2: Synthesis of compound 8A: To a solution of compound 8A-1 (470 mg, 700.78 μmol, 1 eq) in MeOH (10 mL) was added NaOMe (378.58 mg, 7.01 mmol, 10 eq). Stirred at 25 °C for 16 h. LCMS showed complete consumption of starting material, with 47% of desired MS detected. The mixture was poured into saturated aq. NH4Cl (50 mL) and extracted with CH2Cl2 (50 mL × 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The mixture was purified by employing high performance liquid chromatography (pre-HPLC) (column: YMC Triart 30×150 mm×7 μm, mobile phase: [water (aqueous ammonia v / v)-ACN], B%: 0%-60%, 40 min) to obtain compound 8A (70 mg, 104.56 μmol, yield 14.92%, purity 93.3%) as a white solid. MS m / z (ESI): 625 [M+H] + ; 1 H NMR (400 MHz CD3OD), δ ppm 8.41 (s, 2 H) 7.62 - 7.70 (m, 3 H) 7.42 - 7.49 (m, 2 H) 7.37 (d, J = 8.0 Hz, 1 H) 5.45 (br s, 2 H) 4.59 (br s, 2 H) 4.16 (s, 3 H) 3.74 (s, 3 H) 2.08 (s, 6 H).

[0162] Test Example 1. In vitro antagonistic activity screening Cells: HEK293 cells stably expressing human GnRHR (Shanghai Wuxi Apptech New Drug Development Co., Ltd.) Equipment: 384 well plate, Greiner, Vi-cell XR Cell Viability Analyzer, Beckman Coulter, incubator, Thermo.

[0163] Method: HEK293 cells stably expressing human GnRHR were seeded in a 384-well plate at a density of 20,000 / well, and Fluo-4 DirectTM No-wash Loading Buffer (Invitrogen) was added to each well every other day, and then the wells were returned to the incubator and incubated at 37°C for 50 min, and then incubated at room temperature for 10 min. Compounds were measured using a DMSO composition, with 10 μL added to each well, and the measured concentrations were 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.9 nM, 976.6 pM, 244.1 pM, 61.0 pM, 15.3 pM, and 3.8 pM. The fluorescence value was measured using a FLIPR Tetra high-throughput real-time fluorescence detection analysis system. Next, 10 μL of Leuprolide acetate was added, and the fluorescence value was measured. Compound IC 50 ,I C 90 was calculated using Prism, and the results are shown in Table 1.

[0164] Table 1. In vitro antagonistic activity of the compounds of the present invention against human GnRHR TIFF2024540264000034.tif116170 Conclusion: Several compounds of the present invention have obvious inhibitory effects on human GnRHR.

[0165] Test Example 2. In vitro binding screening Cells: Chem-1 cells stably expressing human GnRHR (Eurofins Panlabs Discovery Services) Drugs: 125 I][D-Trp6]-LH-RH, PerkinElmer, [D-Trp6]-LH-RH, Abcam.

[0166] Equipment:MicroBeta2 LumiJET system, PerkinElmer.

[0167] Method: Chem-1 cell membranes stably expressing human GnRHR were resuspended using pH=7.4 HEPES, 6 μg of human GnRHR cell membranes were added to each well, and 0.05 nM [ 125 I]-[D-Trp6]-LH-RH and the test compound were incubated at 25°C for 60 min. Compounds were dissolved in DMSO and the test concentrations were 500 nM, 62.5 nM, 7.81 nM, 0.97 nM, 0.12 nM, 15 pM, and 1.9 pM. For non-specific binding measurements, 1 μM [D-Trp6]-LH-RH was used. Cell membranes were collected by suction filtration and washed, followed by liquid scintillation counting. Compound binding IC 50 ,I C 90 was calculated using Prism, and the results are shown in Table 2.

[0168] Table 2: In vitro binding activity of the compounds of the present invention to human GnRHR TIFF2024540264000035.tif71170 Conclusion: The compounds of the present invention have obvious binding ability to human GnRHR.

[0169] Test Example 3. hERG measurement Cells: CHO cells stably expressing human hERG potassium ion channel (Shanghai Wuxi Apptech New Drug Development Co., Ltd.) Reagents: Physiological Solution (PH=7.4): NaCl 140 mM, KCl 4 mM, CaCl22 mM, MgCl21 mM, Glucose 5 mM, HEPES 10 mM, Osmolarity~298 mOsm, External Solution (PH=7.4): NaCl 80 mM, KCl 4 mM, CaCl22 mM, MgCl21 mM, Glucose 5 mM, NMDG 60mM, HEPES 10mM, Osmolarity~289 mOsm, Internal Solution (PH=7.4): NaCl 10mM, KCl 10mM, KF 110mM, HEPES 10mM, EGTA:10nM, Osmolarity~280mOsm.

[0170] Equipment: QPatch high-throughput fully automated patch clamp system, Sophion.

[0171] Methods: CHO cells stably expressing human hERG potassium ion channel were digested with TrypLE and resuspended using physiological solution. Single-cell high impedance sealing and whole-cell mode formation process was automatically completed by Qpatch. The cell clamp voltage was -80 mV, and a voltage leak of -50 mV for 80 ms was applied, followed by a voltage of +20 mV for 4800 ms to open the hERG channel. Then the voltage was reduced to -50 mV, 5000 ms, and the process was used for data collection and analysis, and finally returned to the clamp voltage (-80 mV, 1000 ms). The process was repeated every 20000 ms. First, 40 μL of solvent control (External Solution+DMSO) was added, and a measurement of 300 ms was performed to collect baseline data. Then, 40 μL of measurement compounds with different concentrations were added, and the measurement process was more than 300 ms. Compounds were dissolved in DMSO and the measured concentrations were 0.30 μM, 1.00 μM, 3.00 μM, 10.00 μM, and 30.00 μM. IC 50 Data was obtained using DataControl, Excel2013, and Prism analysis, and the results are shown in Table 3.

[0172] Table 3: Inhibitory effect of the compounds of the present invention on the human hERG potassium ion channel TIFF2024540264000036.tif87170Conclusion: The inhibitory activity of compounds 1, 2, 2A, 4, 5, 6, 7, and 8A against the human hERG potassium ion channel was equivalent to or less than that of Relugolix, suggesting that the compounds of the present invention have lower cardiotoxicity. Test Example 4. Evaluation of metabolic stability of liver microsomes Liver microsomes: Rat liver microsomes, human liver microsomes Reagents: NADPH, Roche Diagnostics Gmbh, ACN, Merck Chemical, Tolbutamide, Sigma.

[0173] Equipment: Pure water system, Millipore, electronic balance, METTLER TOLEDO, high-speed tabletop centrifuge, Thermo, water bath thermostatic shaker, Shanghai Yiheng Science and Technology Co., Ltd., vortex shaker, Thermo, LC-MS / MS, AB SCIEX.

[0174] Methods: SD rat and human liver microsomes were used to evaluate the metabolic stability of the test substances. The test substances were incubated with NADPH together with liver microsomes of different species under water bath conditions at 37℃, and the reaction was stopped at the designated time points by adding cold acetonitrile solution containing Tolbutamide internal standard, and the samples were pretreated for semi-quantitative analysis by LC-MS / MS. The retention times, chromatogram collection and chromatogram integration of the analyte and Tolbutamide internal standard were processed by using software Analyst (AB Sciex, Framingham, Massachusetts, USA). The ratio of the oversample and internal standard peak areas was converted into the remaining rate to obtain the in vitro elimination rate constant Ke of the sample, and the in vitro elimination rate and half-life of the test substance were calculated, and the results are shown in Table 4.

[0175] Table 4: Results of metabolic stability of compounds of the invention in rat and human liver microsomes TIFF2024540264000037.tif150170 Conclusion: In SD rat liver microsomes, compounds 4 and 5 had low clearance rates, and the other compounds all had moderate clearance rates. In human liver microsomes, compound 3 had a moderate clearance rate, and the other compounds all had low clearance rates.

[0176] Test Example 5. Test substance permeability and transporter primer evaluation Cell: Caco-2 cell Equipment: Water purification system, ELGA LabWate, Biological safety cabinet, NUAIRE, Constant temperature CO2 incubator, Thermo, Microplate reader, PerkinElmer, LC-MS / MS, AB SCIEX.

[0177] Methods: A Caco-2 monolayer cell model was adopted to measure the bidirectional permeability of the test substance and evaluate whether it was transported in vitro by translocation. In the experiment, Caco-2 cells were seeded in a 96-well cell culture plate and used for the transport test after continuous culture for 28 days. The test substance was administered in both directions. After 120 min incubation, samples of apical A, basal B, and cell lysis were collected, and the content of the test substance in the sample was quantitatively measured by liquid chromatography tandem mass spectrometry (LC / MS / MS). From the concentration of the test substance, the apparent permeability coefficient (Papp) and excretion rate in the apical to basal (AB) and basal to apical (BA) directions were calculated, and the results are shown in Table 5.

[0178] Table 5. Permeability results of the compounds of the present invention in Caco-2 cells TIFF2024540264000038.tif104170 Conclusion: Compared with Relugolix, most of the compounds of the present invention have improved permeability in Caco-2 cell experiments, and among them, the excretion rate of compound 2 was improved by nearly 6 times.

[0179] Test Example 6 In vivo pharmacokinetics and tissue distribution study in SD rats Rat: SD rat, male, 200-250 g Equipment: Pure water system, Millipore, electronic balance, METTLER TOLEDO, high-speed tabletop centrifuge, Thermo, water bath thermostatic shaker, Shanghai Yiheng Science and Technology Co., Ltd., vortex shaker, Thermo, LC-MS / MS, AB SCIEX.

[0180] Methods: All compounds were prepared using DMSO and 20% solutol. In the pharmacokinetics study, the intravenous group (iv) was administered at 1 mg / kg, and the intragastric group (ig) was administered at 12 mg / kg. There were three rats in each group, and blood was collected from the orbit of the rats before administration (0 h) and at set times after administration. In the tissue distribution experiment group, a dose of 12 mg / kg was administered intragastrically, and at set times after administration, anesthesia and dissection were performed, cardiac blood was collected, and the pituitary gland was collected by cardiac perfusion. There were three rats at each time point. The plasma was placed in a heparinized EP tube and centrifuged at 13500 rpm for 10 min to separate the plasma. The pituitary gland was homogenized with water at a fixed ratio. After pretreatment of the plasma and pituitary homogenate, analysis was performed by LC-MS / MS to measure the concentrations of the test substance in the plasma and pituitary gland. The plasma drug concentration data was analyzed using WinNonlin (商標) A noncompartmental model was used using Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software. The following pharmacokinetic parameters were calculated using the log-linear trapezoidal method: elimination half-life (T 1 / 2 ), mean in vivo residence time of the drug from time 0 to the end time point (MRT 0-last ), the area under the time-plasma concentration curve from 0 to the end (AUC 0-last ), initial concentration (C0) or maximum concentration C max , and the absolute bioavailability was F. The results are shown in Figures 1 and 2 and Tables 6-1, 6-2, and 6-3.

[0181] Table 6-1 Pharmacokinetic parameters after intravenous administration to SD rats TIFF2024540264000039.tif56170Table 6-2 Pharmacokinetic parameters after intragastric administration in SD rats TIFF2024540264000040.tif58170Table 6-3 Pituitary tissue distribution after intragastric administration (12 mg / kg) in SD rats TIFF2024540264000041.tif86170 Conclusion: (1) In the intragastric administration group, C maxwere 30.7-fold and 3.02-fold higher than those of Relugolix and Compounds 1-9, respectively, and the exposure AUC last were 36.4-fold and 8.80-fold higher than those of Relugolix and Compounds 1-9, respectively. The absolute bioavailability of Compound 1 was improved by 7.79-fold and 4.10-fold compared to those of Relugolix and Compounds 1-9, respectively. The in vivo pharmacokinetic properties of Compound 1 were obviously superior to those of Relugolix and Compounds 1-9.

[0182] (2) In the intragastric administration group, C max , AUC last The total and absolute bioavailability were 3.63-fold, 2.45-fold, and 3.47-fold that of Relugolix, and 1.12-fold, 0.96-fold, and 3.14-fold that of Compound 2A, respectively. The pituitary concentrations of Compound 2 were 2.38-fold, 1.48-fold, and 2.46-fold that of Relugolix, and 8.04-fold, 6.60-fold, and 3.77-fold that of Compound 2A, respectively, at 1 h, 4 h, and 12 h.

[0183] (3) In the intragastric administration group, C max , AUC last and absolute bioavailability were 3.83-, 4.08-, and 3.19-fold that of Relugolix, respectively.

Claims

1. A compound of formula (III), a pharmaceutically acceptable salt or stereoisomer thereof, Among them, X ５ and X ６ is CR ６ or N, and X ５ and X ６ At the same time, CR ６ Or not N, R １ H, D, C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl group, C １ ~C ６ independently selected from haloalkyl groups; R ２ H, D, C １ ~C ６ alkyl group, R ２ａ C substituted with —O— １ ~C ６ independently selected from alkyl groups, R ２ａ is C １ ~C ６ independently selected from haloalkyl groups; R ３ａ , R ３ｅ H, D, halogen, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C ３ ~C ６ cycloalkyl groups, R ４ is H, D, halogen, -CN, -NO ２ , -NH ２ , -OH, -SH, -COOH, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ Haloalkoxy group, C １ ~C ６ Alkylthio group, C １ ~C ６ Alkylamino group, C ３ ~C ６ cycloalkyl groups, R ５ H, D, C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy group, C ３ ~C ６ Cycloalkoxy group, C １ ~C ６ haloalkoxy groups, R ６ H, D, C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ A compound, a pharmaceutically acceptable salt, or stereoisomer thereof, independently selected from haloalkoxy groups.

2. R １ is selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isoamyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, and pentachloroethyl; 2. The compound of claim 1, a pharmaceutically acceptable salt or stereoisomer thereof.

3. R ２ is C １ ~C ６ alkyl group or R ２ａ C substituted with —O— １ ~C ６ alkyl groups, ２ are independently selected from a methyl group, an ethyl group, and a propyl group; R ２ａ are independently selected from a fluoromethyl group, a chloromethyl group, a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, a trichloromethyl group, a 2,2-difluoroethyl group, a 2,2-dichloroethyl group, a 3,3,3-trifluoroethyl group, a 3,3,3-trichloroethyl group, a pentafluoroethyl group, and a pentachloroethyl group; 3. A compound according to any one of claims 1 or 2, a pharmaceutically acceptable salt or stereoisomer thereof.

4. R ３ａ , R ３ｂ , R ３ｃ , R ３ｄ , R ３ｅ are each independently selected from H, D, F, Cl, Br, I, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an s-butyl group, a t-butyl group, an n-pentyl group, an isoamyl group, a neopentyl group, a 1-ethylpropyl group, an n-hexyl group, an isohexyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a 2-ethylbutyl group, a fluoromethyl group, a chloromethyl group, a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, a trichloromethyl group, a 2,2-difluoroethyl group, a 2,2-dichloroethyl group, a 3,3,3-trifluoroethyl group, a 3,3,3-trichloroethyl group, a pentafluoroethyl group, a pentachloroethyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group; 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof.

5. R ４ are H, D, F, Cl, Br, I, -CN, and -NO ２ , -NH ２ , —OH, —SH, —COOH, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, n-pentyl group, isoamyl group, neopentyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 2-ethylbutyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group a methyl group, a trichloromethyl group, a 2,2-difluoroethyl group, a 2,2-dichloroethyl group, a 3,3,3-trifluoroethyl group, a 3,3,3-trichloroethyl group, a pentafluoroethyl group, a pentachloroethyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentyloxy group, an S-pentyloxy group, a hexyloxy group, a 2-ethylbutoxy group, a fluoromethoxy group, a chlorometh oxy group, difluoromethoxy group, dichloromethoxy group, trifluoromethoxy group, trichloromethoxy group, 2,2-difluoroethoxy group, 2,2-dichloroethoxy group, 3,3,3-trifluoroethoxy group, 3,3,3-trichloroethoxy group, pentafluoroethoxy group, pentachloroethoxy group, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, sec-butylthio group, tert-butylthio group, n-pentylthio group , S-pentylthio group, hexylthio group, 2-ethylbutylthio group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, sec-butylamino group, tert-butylamino group, n-pentylamino group, S-pentylamino group, hexamino group, 2-ethylbutylamino group, cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group, 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof.

6. R ５ represents H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isoamyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, and pentafluoroethyl groups. , a pentachloroethyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentyloxy group, an S-pentyloxy group, a hexyloxy group, a 2-ethylbutoxy group, a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, a fluoromethoxy group, a chloromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a 2,2-difluoroethoxy group, a 2,2-dichloroethoxy group, a 3,3,3-trifluoroethoxy group, a 3,3,3-trichloroethoxy group, a pentafluoroethoxy group, and a pentachloroethoxy group; 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof.

7. R ６ is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an s-butyl group, a t-butyl group, an n-pentyl group, an isoamyl group, a neopentyl group, a 1-ethylpropyl group, an n-hexyl group, an isohexyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a 2-ethylbutyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a fluoromethyl group, a chloromethyl group, a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, a trichloromethyl group, a 2,2-difluoroethyl group, a 2,2-dichloroethyl group, a 3,3,3-trifluoroethyl group, a 3,3,3 independently selected from a trichloroethyl group, a pentafluoroethyl group, a pentachloroethyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentyloxy group, an S-pentyloxy group, a hexyloxy group, a 2-ethylbutoxy group, a fluoromethoxy group, a chloromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a 2,2-difluoroethoxy group, a 2,2-dichloroethoxy group, a 3,3,3-trifluoroethoxy group, a 3,3,3-trichloroethoxy group, a pentafluoroethoxy group, and a pentachloroethoxy group; 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof.

8. A compound of formula (II), a pharmaceutically acceptable salt or stereoisomer thereof, Among them, X １ is independently selected from O or S; X ２ and X ３ is CR ４ or N, X ５ is independently selected from CH or N; R １ H, D, C １ ~C ６ independently selected from alkyl groups, R ２ is R ２ａ independently selected from a methyl group, an ethyl group, an n-propyl group, and an n-butyl group substituted with —O—; R ２ａ are independently selected from a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, and a trichloromethyl group; R ３ａ , R ３ｅ are each independently selected from H, D, fluorine, chlorine, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, and a trichloromethyl group; R ４ are independently selected from H, D, fluorine, chlorine, a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy group, a fluoromethoxy group, a chloromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a methylthio group, an ethylthio group, an n-propylthio group, an n-butylthio group, a methylamino group, an ethylamino group, an n-propylamino group, and an n-butylamino group; R ５ are independently selected from H, D, methyl, ethyl, n-propyl, n-butyl, methoxy, ethoxy, n-propoxy and n-butoxy groups; A compound, a pharmaceutically acceptable salt or stereoisomer thereof.

9. A compound of formula (II), a pharmaceutically acceptable salt or stereoisomer thereof, Among them, X １ is independently selected from O or S; X ２ is CR ４ Independently selected from the R ４ are independently selected from a fluoromethoxy group, a chloromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a trifluoromethoxy group, and a trichloromethoxy group; X ３ is CR ４ Independently selected from the R ４ are independently selected from fluorine and chlorine; X ５ is independently selected from CH or N; R １ H, D, C １ ~C ６ independently selected from alkyl groups, R ２ is R ２ａ independently selected from a methyl group, an ethyl group, an n-propyl group, and an n-butyl group substituted with —O—; R ２ａ are independently selected from a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, and a trichloromethyl group; R ３ａ , R ３ｅ are each independently selected from H, D, fluorine, chlorine, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, and a trichloromethyl group; R ４ are independently selected from H, D, fluorine, chlorine, a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy group, a fluoromethoxy group, a chloromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a methylthio group, an ethylthio group, an n-propylthio group, an n-butylthio group, a methylamino group, an ethylamino group, an n-propylamino group, and an n-butylamino group; R ５ are independently selected from H, D, methyl, ethyl, n-propyl, n-butyl, methoxy, ethoxy, n-propoxy and n-butoxy groups; A compound, a pharmaceutically acceptable salt or stereoisomer thereof.

10. The following compound, its pharmaceutically acceptable salt or stereoisomer: Selected from A compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

11. A compound according to any one of claims 1, 8 to 10, a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier. Drug composition.

12. Use of a compound according to any one of claims 1, 8 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof in the preparation of a medicament for the treatment of a sex hormone dependent disease.

13. The sex hormone dependent diseases include sex hormone dependent cancer, bone metastasis of sex hormone dependent cancer, prostatic hyperplasia, prostate cancer, uterine cancer, breast cancer, pituitary cancer, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, acne, alopecia, Alzheimer's disease, infertility, irritable bowel syndrome, benign or malignant tumors that are hormone independent and sensitive to LH-RH (luteinizing hormone releasing hormone), or flushing.

13. The use according to claim 12.

14. Use of the compound according to any one of claims 1, 8 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof in the preparation of a reproductive regulator, a contraceptive, or an ovulation inducer, or in the preparation of a drug for preventing postoperative recurrence of sex hormone-dependent cancer.

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